Reproductive endocrinology and metabolism
Our group’s research activities aim to yield new key information on the pathophysiology of polycystic ovary syndrome (PCOS), the most common female endocrine and metabolic disorder.
Its etiology is not well understood, but genetic, epigenetic, and environmental factors have been implicated in its development. We also investigate the effect and mechanisms of acupuncture and/or exercise on reproductive function, hyperandrogenemia and insulin resistance as well as on key molecular pathways and epigenetic modifications in adipose and skeletal muscle tissues.
Developmental origin of androgen excess, insulin resistance and behavioral dysfunction in females
The etiology of PCOS is not well understood but emerging evidence suggests that PCOS originates, at least in part, in fetal life and elevated maternal androgens and/or maternal obesity have been implicated to play a role, however the mechanisms are largely unknown. Maternal sex steroids and metabolic hormones regulate placental steroidogenesis and the transport of nutrients, functions that are critical for fetal growth and development. Maternal androgen excess and obesity might alter metabolism, sex steroid levels and nutrition delivery to the fetus via the placenta. In this project we propose that changes in placental function are involved in the intrauterine programming of PCOS.
The overall hypothesis is that high maternal androgens and maternal obesity up-regulate placental steroid receptors and steroidogenic enzymes, which in turn alter metabolic pathways and contribute to the development of PCOS and related symptoms in the offspring.
Transgenerational germline inheritance of disease
Our exciting preliminary data in mice demonstrate that maternal androgen exposure and diet-induced maternal obesity cause sexual dimorphic transgenerational reproductive, behavioural and metabolic dysfunction in great-grandchildren (F3 generation). Noteworthy, these experiments did not distinguish between environmental changes in utero and epigenetic factors in germ cells. Currently we investigate if epigenetic inheritance via the germline cells themselves leads to the transgenerational increase in offspring’s susceptibility to reproductive, metabolic, and behavioral phenotypic traits. We also investigate if the acquired androgen and/or diet-induced epigenetic traits in the germline cells can be reversed by exercise and thus prevent the transmission of disease susceptibility to the following generations.
Genome-wide DNA methylation and gene expression profiles in adipose and skeletal muscle tissue from women with and without PCOS
The possibility of an epigenetic component of PCOS has only recently been explored. Interestingly, epigenetic modification of PGC-1α has been reported in granulosa cells from women with PCOS and a genome-wide methylation array of adipose tissue from prenatally androgenized female rhesus monkeys showed changes in methylation of genes in the TGF-β superfamily. These observations suggest that epigenetic modifications could be involved in diseases such as PCOS.
This project aims to investigate differences in genome-wide gene expression and DNA methylation pattern in subcutaneous adipose tissue and skeletal muscle from women with and without PCOS. To investigate the importance of differential expression in adipose tissue, selected genes are biologically validated in a second case-control cohort matched for age, weight and BMI.
To elucidate the effect and mechanisms of acupuncture and exercise on insulin resistance and key signaling pathways in adipose and skeletal muscle tissue in translational studies
Because women with PCOS require long-term treatment and current treatments often have severe metabolic and gastrointestinal side effects, there is a need for novel treatment options. Physical exercise and acupuncture with low-frequency electrical stimulation, both induces ovulation and decreases circulating androgens. In this project, we hypothesize that acupuncture treatment with muscle contractions, by reducing hyperandrogenemia and reversing insulin resistance, can modify key molecular alterations and epigenetic changes to the genomic DNA in adipose tissue and skeletal muscle to the same extent as exercise.
Further, as the effect of acupuncture with low-frequency electrical stimulation are hypothesized to be mediated via sympathetic nervous system and/or dopaminergic system, we will administer blockers of α-adrenoceptor, β-adrenoceptor or dopamine1(D1)receptor, to elucidate which key signaling pathways mediate the effect in ovaries, adipose tissue and skeletal muscle.
Elisabet Stener-Victorin – Professor, Research group leader
Romina Fornes – Postdoc
Eva Lindgren – Research Engineer
Maria Manti – PhD student
Haojiang Lu – Research assistant
Sanjiv Risal – Postdoc
Former group members
Min Hu – Postdoc
Milana Kokosar – PhD student
Lisa Lindheim – PhD Candidate, Medical University of Graz, Austria
Rodrigo Marcondes – PhD student
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
- Swedish Research Council
- Novo Nordisk Foundation
- Strategick Research Program of Diabetes (SRP Diabetes)
- Karolinska Institutet
- ALF 2015-2017
- Professor Charlotte Ling, Lund University
- Professor Inger Sundström-Pooroma, Uppsala University
- Professor Claes Ohlsson, University of Gothenburg
- Professor Angelica Lindén Hirschberg, Karolinska Institutet
- Professor, Kurt Højlund, Diabetes Research Center, Odense University, Denmark
- Professor Eszter Vankey, Norweigan University of Science and Technology, Trondheim, Norway
- Professor Matti Poutanen, Turku University, Finland
- Associate Professor, Laure Morin Papunen, University of Oulu, Finland
- Professor, Richard Legro, Pennsylvania State University, US
Transcriptional and Epigenetic Changes Influencing Skeletal Muscle Metabolism in Women With Polycystic Ovary Syndrome.
Nilsson E, Benrick A, Kokosar M, Krook A, Lindgren E, Källman T, et al
J. Clin. Endocrinol. Metab. 2018 Dec;103(12):4465-4477
Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring.
Manti M, Fornes R, Qi X, Folmerz E, Lindén Hirschberg A, de Castro Barbosa T, et al
FASEB J. 2018 08;32(8):4158-4171
Effect of exposure to second-hand smoke from husbands on biochemical hyperandrogenism, metabolic syndrome and conception rates in women with polycystic ovary syndrome undergoing ovulation induction.
Li J, Wu Q, Wu XK, Zhou ZM, Fu P, Chen XH, et al
Hum. Reprod. 2018 04;33(4):617-625
A Single Bout of Electroacupuncture Remodels Epigenetic and Transcriptional Changes in Adipose Tissue in Polycystic Ovary Syndrome.
Kokosar M, Benrick A, Perfilyev A, Nilsson E, Källman T, Ohlsson C, et al
Sci Rep 2018 01;8(1):1878
Acupuncture for Infertility in Polycystic Ovary Syndrome-Reply.
Wu XK, Stener-Victorin E, Zhang H
JAMA 2017 10;318(15):1502
The effect of androgen excess on maternal metabolism, placental function and fetal growth in obese dams.
Fornes R, Maliqueo M, Hu M, Hadi L, Jimenez-Andrade JM, Ebefors K, et al
Sci Rep 2017 08;7(1):8066
Adiponectin protects against development of metabolic disturbances in a PCOS mouse model.
Benrick A, Chanclón B, Micallef P, Wu Y, Hadi L, Shelton JM, et al
Proc. Natl. Acad. Sci. U.S.A. 2017 08;114(34):E7187-E7196
Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome: A Randomized Clinical Trial.
Wu XK, Stener-Victorin E, Kuang HY, Ma HL, Gao JS, Xie LZ, et al
JAMA 2017 06;317(24):2502-2514
Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture.
Benrick A, Kokosar M, Hu M, Larsson M, Maliqueo M, Marcondes RR, et al
FASEB J. 2017 08;31(8):3288-3297
Exercise differentially affects metabolic functions and white adipose tissue in female letrozole- and dihydrotestosterone-induced mouse models of polycystic ovary syndrome.
Marcondes RR, Maliqueo M, Fornes R, Benrick A, Hu M, Ivarsson N, et al
Mol. Cell. Endocrinol. 2017 06;448():66-76
Main supervisor: group leader Elisabet Stener-Victorin
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