Reproductive endocrinology and metabolism – Elisabet Stener-Victorin's research group

Our group's research activities aim to yield new key information on the pathophysiology of polystic ovary syndrome (PCOS), the most common female endocrine and metabolic disorder.

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About us

An illustration of PCOS from Stener-Victorin et al. Endocr Rev, 2020,41:4; 538–576
Stener-Victorin et al. Endocr Rev, 2020,41:4; 538–576

Our research aims to gain deeper understanding of the heritability of PCOS and associated comorbidities such as type 2 diabetes and mental-health disorders across generations by dissecting the molecular, mechanistic, and causal links, and to determine whether men can also transmit the disease. We use different PCOS-like mice models to delineate the main trigger of PCOS and define whether germ cells drive the transmission of the syndrome in the absence of PCOS-associated gene variants. Moreover, we translate our findings in mice to the clinical situation and perform detailed phenotyping of women with and without PCOS and collect serum/blood and endometrium, fat and skeletal muscle tissue biopsies and investigate the effect of different treatments.

Link to the article

Group members

Elisabet Stener-Victorin

Research group leader

I completed my PhD in the field of reproductive endocrinology at the University of Gothenburg (GU). This was followed by postdoctoral studies in Japan followed by research position at GU funded by Swedish Research Council (VR). 2015 I was recruited to the Department of Physiology and Pharmacology at KI and I moved with my research group. I am PI for the Reproductive Endocrinology and Metabolism (REM)-group and our research focus on dissecting genetic versus epigenetic heritability in the transmission of PCOS and associated comorbidities such as type 2 diabetes, endometrial dysfunctions, and mental-health disorders across generations by dissecting the molecular, mechanistic, and causal links, and to determine whether men can also transmit the disease. Recently we also start to investigate the role of the immune system in the pathology of PCOS.

Location: Biomedicum B0552

Sara Torstensson

PhD student

I have a Master of Science in Biomedicine and the overarching objective of my PhD project is to determine the role of the immune system in the pathology of polycystic ovary syndrome (PCOS). Using various in vivo models, I aim to characterize the immune profile and study the underlying mechanisms as well as the risk of transgenerational transmission.

Location: Biomedicum B0551

Haojiang Lu

PhD student

I have a Master of Science in Biomedicine and in my PhD I am studying the transgenerational inheritance of PCOS-like phenotypes in both male and female offspring; and trying to dissect possible mechanisms of such transmission. Mouse models are important part of my project, while in vitro experiments and sequencing techniques are also applied with the help of specialists.

Location: Biomedicum B0553

Gustaw Eriksson

PhD student

I have a Master of Science in Bioinformatics at Lund University, and I start my PhD studies in the Reproductive Endocrinology and Metabolism (REM) group during the fall 2021. My main objective is to generate and analyze single cell sequencing data from tissue biopsies from women with and without PCOS. Moreover, we have recently established endometrial organoids to unravel underlying mechanisms.

Location: Biomedicum B0553

Congru Li

PhD, Postdoc

I completed my PhD of Genetics at Chinese Academy of Sciences in Beijing. My research interest focusing on the epigenetic mechanisms of female reproductive diseases including embryo development and offspring health. I have experience and expertise in epigenetic and transcriptomic single cell and bulk sequencing and bioinformatic analysis.  I am involved in single cell RNA sequencing and DNA methylation of tissue biopsies from women with and without PCOS.

Location: Biomedicum B0553

Eva Lindgren

MSc, Research Engineer

I have a bachelor’s degree in biomedical laboratory science and started to work at KI 1980. Since 2016 I am working as Lab manager in the REM group. I have many administrative tasks in the group, and contributing to many of the research project, specifically the human cell culture projects.

Location: Biomedicum B0551

Anja Dekanski

Research assistant

I am a PhD student at the Reproductive Endocrinology and Metabolism group lead by Elisabet Stener-Victorin. I come from Serbia, I graduated from Karolinska Institutet's Master in Biomedicine in 2023, and did my Bachelor degree at University College Maastricht in the Netherlands.

My current research focuses on understanding cellular-level functional changes in adipose and endometrium tissue from women with polycystic ovary syndrome. I work mostly with primary human adipose and endometrium cell cultures, including in vitro differentiation and organoids. However, my work also includes basic sequencing-based bioinformatics and clinical data analysis.

Tina Gorsek Sparovec

PhD, Postdoc

I completed my PhD in Obstetrics and Gynecology at the Medical University of Graz. The overarching objective of my post doctoral project is to dissect molecular, mechanistic and casual links that contribute to skeletal muscle dysfunction in PCOS. Using state-state-of-the-art approaches including single nuclei RNA sequencing, extracellular vesicles and in vitro cell culture models from our unique cohort, I aim to identify PCOS-specific fingerprint in skeletal muscle and underlying changes in tissue cross talk.

Publications

Selected publications

All publications from group members

Staff and contact

Group leader

All members of the group

Former group members

Angelo Ascani - PhD
Elizabet Jedel – PhD
Julia Johannson – PhD
Lisa Lindheim – PhD Candidate, Medical University of Graz, Austria
Louise Mannerås Holm – PhD
Luigi Manni – PhD
Min Hu – Postdoc
Milana Kokosar – PhD student
Maria Manti – PhD
Rodrigo Marcondes – PhD student
Romina Fornes – Postdoc
Sanjiv Risal - PhD
Yang Qian – PhD
Zhiyi Zhang, PhD, visiting researcher from Shandong Provincial Qianfoshan Hospital, Jinan, China

Group members outside Karolinska Institutet

Anna Benrick – MSc, PhD, Researcher, Gothenburg University, Sweden
Emma A. Nilsson – Researcher, PhD, Lund University
Josefin Katakoa – Doctoral student, Gothenburg University, Sweden
Manuel Maliqueo – PhD, University of Chile, Santiago

Collaborations

National collaborators

International collaborators

  • Professor Richard Legro, Pennsylvania State University, US
  • Professor Andrea Dunaif, Icahn School of Medicine and Mount Sinai Health System, US
  • Professor Thomas Jansson, University of Colorado Denver, US
  • Professor Helena Teede, Monash University, Australia
  • Professor Adam Balen, Leeds University Hospital, UK
  • Professor Jie Qiao, Peking University Third Hospital, China
  • Professor Matti Poutanen, Turku University, Finland
  • Nordic PCOS Network: Dorte Glintborg and Marianne Andersen, Odense University, DK; Eszter Vanky, NTNU Trondheim, Norway; Terhi Piltonen and Laure Morin Papunen, University of Oulu, Finland; Juha Tapanainen, University of Helsinki

Research projects

An illustration of PCOS
Stener-Victorin and Deng. Nature Review Endocrinology, 2021.

Polycystic ovary syndrome (PCOS) is linked to reproductive and metabolic disturbances as well as to mental health conditions such as anxiety and depression. Our research aims to gain deeper understanding of the etiology and heritability of PCOS and associated comorbidities such as type 2 diabetes, endometrial dysfunction, and mental-health disorders across generations by dissecting the molecular, mechanistic, and causal links, and to determine whether men can also transmit the disease.

Delineate the roles of different androgen triggers and molecular pathways that drive transgenerational transmission of PCOS-like traits

We know that hyperandrogenemia plays a key pathogenic role and that PCOS runs in families, with an estimated heritability of 70%. In a register-based study of nearly 30,000 daughters of women with or without PCOS, we found that daughters of women with PCOS have a five-fold increased risk of being diagnosed with the syndrome (Risal et al. Nature Medicine, 2019). But how PCOS is inherited remains unclear.

An illustration from Stener-Victorin and Deng. Nature Review Endocrinology, 2021.
Stener-Victorin and Deng. Nature Review Endocrinology, 2021.

Accumulating evidence suggests that an epigenetic process triggered by an adverse maternal-fetal environment could yield the same phenotypic heritability as conventional genetics. Recently we made the discovery that PCOS-like traits induced by maternal androgen-exposure (Risal et al. Nature Medicine, 2019) can be passed on in mice from mothers (F0) to daughters (F1), granddaughters (F2), and even to great-granddaughters (F3), and that transcriptional and mitochondrial perturbations of oocytes accompany the transgenerational transmission. These intriguing findings raise the possibility that epigenetic modifications carried by germ cells and/or somatic cells can transmit PCOS across multiple generations. But they do not account for how males are affected and for the genetic contribution of the inheritance. Neither do these experiments disentangle the contribution of germ cells from that of the in utero environment in driving transgenerational transmission of PCOS.

Illustration from Stener-Victorin and Deng. Nature Review Endocrinology, 2021.
Stener-Victorin and Deng. Nature Review Endocrinology, 2021.

Define cell-type-specific disease signatures in endometrium, adipose and skeletal muscle tissues

Despite increasing evidence that multiple aspects of adipose tissue, skeletal muscle, and endometrial dysfunctions in women with PCOS are regulated by both genetic and epigenetic mechanisms, the contribution of cellular heterogeneity to these tissue dysfunctions is unclear. To gain insight into the cellular complexity and to tease apart genetic and epigenetic influence, we will characterize gene expression and DNA methylation at the single-cell level in endometrial, skeletal muscle and adipose tissues of women with and without the syndrome.

An illustration of research of PCOS
Define cell-type-specific disease signatures in endometrium, adipose and skeletal muscle tissues

Establishment of endometrial organoids and adipocyte spheroids

Endometrial organoids (EOs) and adipocyte spheroids (ASs) circumvent constraints associated with fresh tissue and are unique powerful tools for pathophysiological research, functional testing of cell-type-specific disease markers, and drug screening of novel therapeutic targets. We establish EOs of endometrial tissue and ASs of adipose tissue (in collaboration with Carolina Hagberg, KI) of women with PCOS and controls. These will be used to test how e.g. sex steroids and/or insulin affect altered signaling pathways identified by cell-type specific large-scale sequencing.

 

An illustration of immunoflourscence.
Endometrial organoids

To elucidate the effect and mechanisms of metformin and acupuncture on insulin resistance and key signaling pathways in target tissues in women with PCOS

Prevention of PCOS is limited and management inadequate due to lack of mechanistic insights of PCOS. Changes in diet and lifestyle is the first choice for improving insulin sensitivity and preventing type 2 diabetes. Metformin is used in those with impaired glucose tolerance and type 2 diabetes who do not respond to lifestyle changes and works mainly by reducing hepatic gluconeogenesis and to a lesser extent by increasing glucose uptake in skeletal muscle and adipose tissue. An alternative approach to metformin and exercise is electroacupuncture treatment. We have in an uncontrolled study showed that repeated low-frequency electroacupuncture improves insulin sensitivity, decreases excess androgen levels, and restores altered epigenetic and transcriptional changes in adipose tissue and that the effect is mediated by neuronal circuits in the sympathetic and endocrine system. Moreover, our recent findings provide evidence that a single bout of electroacupuncture normalizes gene expression in skeletal muscle in a manner like acute exercise. Electroacupuncture might therefore be a useful way of assisting those who have difficulties performing exercise. In an on-going randomized control (RCT) (NCT01457209) we investigate the effectiveness of metformin, low-frequency electroacupuncture, and lifestyle management for improving insulin sensitivity in women with PCOS. Moreover, we explore whether these treatments can remodel transcriptional changes and restore molecular dysfunctions and in endometrium, adipose tissue and skeletal muscle tissue biopsies at baseline, after 16 weeks of treatment and at follow up to advance our understanding of PCOS-specific insulin resistance.

Determine the role of the immune system in the pathology of PCOS

Women with PCOS suffer from chronic low-grade inflammation and some even develop autoimmune diseases, which are further aggravated by metabolic disturbances that characterize the syndrome. Accumulating evidence suggests a link between PCOS and immune responses, but whether the observed immune hyperactivation is a cause or consequence of hyperandrogenism, and whether this immunophenotype is passed on to subsequent generations is unknown.  To investigate what role the immune system play in the pathology of PCOS we currently investigate whether:

  1. Transfer of self-reactive IgG from women with PCOS to mice induce a PCOS-like phenotype?
  2. Characterize immunophenotype in androgen-induced PCOS mice.
  3. Determine whether transferring B cells from androgen-induced PCOS mice to reconstituted B-null mice induces development of a PCOS-like immunophenotype.
An illustration how to determine the role of the immune system in the pathology of PCOS
Determine the role of the immune system in the pathology of PCOS

Dissertations

Main supervisor: group leader Elisabet Stener-Victorin

2020 – Maria Manti, MSc, Nutrition Science
The Title of the thesis: Developmental origins of polycystic ovary syndrome: Role of early adverse life events on adult health.  Department of Physiology and Pharmacology, Karolinska Institutet

2018 – Milana Kokosar, Msc Pharmacy. PhD.
Title of PhD project: Polycystic ovary syndrome – Androgen Excess and Insulin resistance in women: Identification of molecular targets to improve glucose homeostasis. Institute of Neuroscience and Physiology, Endocrinology, University of Gothenburg.

2017 – Romina Fornes, Msc Reprod Biology and Midwife. PhD.
Title of PhD project: Polycystic ovary syndrome – Role of androgens and obesity on placenta function and fetal development. Department of Physiology and Pharmacology, Karolinska Institutet

2013 – Julia Johansson, Msc Medical Engineering. PhD.
Title of thesis: Polycystic ovary syndrome - Effect of acupuncture on insulin resistance and neuroendocrine function. Institute of Neuroscience and Physiology, Endocrinology, University of Gothenburg.

2010 – Elizabeth Jedel, PhD.
Title of thesis: Polycystic Ovary Syndrome: Studies of affective symptoms in association with sex steroids and evaluation of electroacupuncture and physical exercise. Institute of Clinical Neuroscience, OCIM, Karolinska Institute, Stockholm.

2010 – Louise Mannerås Holm, PhD.
Title of thesis: Polycystic ovary syndrome: Studies of metabolic and ovarian disturbances and effects of physical exercise and electro-acupuncture. Institute of Neuroscience and Physiology, University of Gothenburg.

2009 – Lena Svedberg, PhD.
Title of thesis: Cold feet in children with neurological disorders. Institute of Neuroscience and Physiology, University of Gothenburg.

2007 – Annika Billhult, PhD.
Title of thesis: The effect of massage for women with breast cancer. Institute of Neuroscience and Physiology, University of Gothenburg.

2005 – Luigi Manni, PhD.
Title of thesis: Adrenoceptors and Nerve Growth Factor: Effects of Electro-Acupuncture and Physical Exercise in Rats with Steroid-Induced Polycystic Ovaries. Cardiovascular Institute, University of Gothenburg