Reproductive endocrinology and metabolism group ongoing projects.
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.
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.
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.
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.
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:
- Transfer of self-reactive IgG from women with PCOS to mice induce a PCOS-like phenotype?
- Characterize immunophenotype in androgen-induced PCOS mice.
- Determine whether transferring B cells from androgen-induced PCOS mice to reconstituted B-null mice induces development of a PCOS-like immunophenotype.