Research Areas

Novel signalling and treatments in male and female infertility

Fertility issues are a major global concern, affecting millions of couples worldwide. Approximately 15% of couples experience difficulties conceiving, making infertility one of the most common health problems among people of reproductive age. The causes are complex and multifactorial, often involving hormonal imbalances, genetic factors, lifestyle influences, and environmental exposures. The aim of our research is to characterise novel signalling pathways involved in male and female infertility, with a specific focus on understanding the role of bone factors such as FGF23 and RANKL as key regulators of reproductive function. We are particularly interested in the molecular and cellular mechanisms through which minerals and some of these skeletal factors influence gonadal development, gametogenesis, and hormonal regulation in both sexes, as well as its potential contribution to infertility in various pathological conditions. Using a translational combination of in vitro, ex vivo and randomized human clinical trials, we manipulated minerals or one of these skeletal factors and its downstream signalling components to determine their effects on germ cell development, steroidogenesis, and overall reproductive health. Currently we are focusing on how minerals, skeletal factors and gonadotropins influence gonadal function with the ultimate aim of developing medical treatment that can improve fertility in some infertile couples.

Novel treatment options for menopause

Women's health has not been prioritized in research in the previous years, and even though Menopausal Hormone Therapy (MHT) is a good and well-established treatment option for menopausal symptoms, the risk profile of MHT makes a lot of women refusing to take the medication and are thus suffering from both severe vasomotor symptoms (VMS), but also cardiovascular disease and osteoporosis. We therefore aim to investigate and explore novel treatment options for postmenopausal women and have identified Luteinizing Hormone (LH) as a key player during perimenopause and menopause. We have now developed an inhibitor of LH and are currently testing if this treatment can be used to alleviate some of the symptoms and complications of menopause. Moreover, we are trying to understand how androgen production is being regulated during menopause. We are also running clinical trials in menopausal women comparing 4 different treatments simultaneously to elucidate the ideal treatment for any specific symptom or complication.

Endocrine cross-talk

Endocrine crosstalk refers to interactions between endocrine and non-endocrine tissues that extend beyond traditional gland-to-target pathways. A key example is the interplay between bone and the gonads, which regulates hormonal balance, metabolism, and reproduction.

Bone, now recognized as an endocrine organ, secretes FGF23, RANKL, OPG, osteocalcin, and these factors may influence gondal function and steorid hormones production. In turn, the gonads regulate bone metabolism through sex hormones. Fat tissue, another endocrine organ, contributes to this crosstalk by secreting leptin, which regulates both bone mass and reproductive function through gonadotropin-releasing hormone (GnRH) secretion. From here, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary play a role in both reproductive and skeletal health. Interestingly, disruptions in this crosstalk, which seems to be highligh relevant in conditions such as menopause or hypogonadism, can therefore contribute to bone loss and osteoporosis.

Minerals like calcium, magnesium, and phosphate, regulated by bone-derived fibroblast growth factor 23 (FGF23), vitamin D, and parathyroid hormone (PTH), further integrate these systems. Proper mineral homeostasis is essential for both bone integrity and reproductive function, as imbalances can impair fertility and skeletal strength. Moreover, we have found that minerals and skeletal factrors also influence pituitary function and thereby highlights the complexcity of endocrine crosstalk.Understanding these complex, non-classical endocrine interactions provides new therapeutic targets for not only osteoporosis, but also infertility, and metabolic disorders.

Rare mineral and bone disorders

Abnormalities in serum calcium concentration can have profound effects on the neurological, gastrointestinal, and renal function. The maintenance of normal serum calcium levels is a result of tightly regulated ion transport by the kidneys, intestinal tract, and bones, mediated by hormones, especially parathyroid hormone and vitamin D.

Our research seeks to understand the mechanisms responsible for abnormalities in the calcium homeostasis. This includes characterization of pathogenic variants inherited in families in genes involved in the control of systemic calcium levels such as AP2S, CASR and GNA11, as well as also other causes of disturbed calcium homeostasis such as granulomatous disorders and inherited disorders of mineral disease.

These studies enhance our understanding of the body’s regulation of mineral levels and can guide us to the most effective therapy.

Ectopic calcifications in cancer and benign disease

Many solid cancers are linked with calcifications within the adjacent normal tissue and these calcifications can often be visualized using imaging techniques and may increase the likelihood for taking a biopsy of the given tissue. Calcifications are frequent findings in the thyroid, kidney, testicles, prostate, breast, and uterus, but the composition of these calcifications vary and the etiology of them are largely unknown. Most studies find that microcalcifications consisting of hydroxyapatite (Calcium and phosphate crystals incl bone like proteins) have been associated with an increased risk of cancer although can also be the result of benign causes. We have shown thats loss-of-function variants in the phosphate transporter gene SLC34A2 or aberrant expression of fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis, can lead to deposition of hydroxyapatite. This indicates that local mineral homeostasis is essential for deposition of hydroxyapatite and understanding etiology may help to determine when macrocalcifications are linked with benign conditions and cancer and thereby help In selecting the correct patients for biopsy in patients with tumors in thyroid or breast. Moreover, understanding how these calcifications occur can be used therapeutically for instance in prostate cancer patients where surgery has serious adverse effects and maybe induction of calcifications in specific areas of the prostate can be used to eradicate dormant prostate cancer without performing surgery.

Characterisation of signalling directing the development and function of fetal gonads and adrenals

Significant progress has been made in the overall understanding of the cellular and molecular mechanisms directing organ development in mammalian species. However, our knowledge of the specific features of human embryogenesis is mostly based on anatomical data combined with extrapolations from mouse models. Thus, functional human ex vivo culture models are essential for understanding the normal functioning of the human body and its disruption in patients suffering from congenital diseases.
The aim of our research in this area is to characterise the signalling pathways directing human fetal testis, ovary and adrenal development - in normal development and in disease. In particular, we are interested in the molecular and cellular mechanisms that promotes sex-specific human fetal gonad differentiation, fetal germ cell differentiation in ovaries and testes as well as the regulation of endocrine function in human fetal adrenals and gonads. Using ex vivo our established and extensively validated tissue culture approaches we specifically manipulate selected signalling pathways involved in sex-specific differentiation of the gonads, cell lineage specification, and the sex-specific fetal germ cell development – to examine effects on gonadal development, morphology, and endocrine and paracrine function. Additionally, in ex vivo tissue culture of human fetal adrenals we examine the effects of selected drugs and exposures on adrenal steroidogenesis including both classic and non-classic pathways. Thus, aiming to explore the contribution and importance of the alternative (backdoor) and 11-oxygenated androgens in human fetal adrenal function.

Medical treatment of nephrolithiasis

In collaboration with Dr. Ebbe Eldrup more than 200 patients with foreign body granuloma disease are seen in our clinical department. Almost 50% of these patients develop kidney stones although most of them have normocalcemia. We are trying to undertand the mechanism for this and will be running a clinical trial to test whether we can reduce this risk with renoprotective medication.

Establishing ex vivo cultures of thyroid and adrenal glands

Our group has established ex vivo tissue cultures of multiple organs to study the organ function during development, tumor formation and how various factors influence the specific organs. In the years to come, our overall aim is to develop ex vivo cultures of adult human adrenal and thyorid tissue to test specific treatments on these organs before applying them in clinically relevant patient groups.