COMPASS - Copenhagen Menopause Study 
Women experience hormonal changes throughout their lives. The first occurs at puberty with the onset of the menstrual cycle, followed by pregnancy, and finally during the transition to and throughout menopause. Eighty percent of women going through menopause experience symptoms such as hot flashes and night sweats, known as vasomotor symptoms (VMS). Menopausal symptoms have a significant impact on women’s physical and mental health. Sixty-six percent of women in Western countries are overweight, which increases the risk of comorbidities such as metabolic syndrome, type 2 diabetes, and atherosclerosis with associated cardiovascular diseases. At the same time, 54% of women have osteoporosis, which—due to the increased risk of fractures—results in excess mortality. These diseases and conditions pose a considerable economic burden on society.
This study is a single-blinded, randomized clinical trial over 8 weeks with 4 parallel groups, comparing the effect of a gonadotropin-releasing hormone (GnRH) analog with placebo and with two additional treatment arms using transdermal estrogen gel or testosterone gel. The primary endpoint is a change in bone turnover markers to investigate whether any of these treatments can halt bone degradation. Secondarily, the study examines whether any of the treatments can reduce VMS related to menopause, how they affect metabolism, whether they can prevent weight gain, or reduce the risk of endocrine diseases such as type 2 diabetes and primary hyperparathyroidism. Should you consider becoming a project participant you can contact us via this webpage.
NOVA-NOA A Novel Aromatase Inhibitor
NOVA NOA is a single-center, sponsor-investigator-initiated intervention trial. Men with non-obstructive azoospermia will receive Leflutrozole 0.3 mg once weekly for a total of 20 weeks. The primary endpoint is proportion of patients with spermatozoa in the ejaculate at Week 12-20.
Link to ClinicalTrials.gov
FITMI - First In Treating Male Infertility 
FITMI is a sponsor-investigator-initiated, double-blinded, placebo-controlled 1:1, single-center, randomized clinical trial. Men with oligospermia were randomized to receive either a single-dose denosumab 60 mg subcutaneous injection or placebo. The study will be carried out at the Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen. The primary outcome of the study is defined as the difference in sperm concentration (millions pr. mL) one spermatogenesis (80 days) after inclusion.
Link to ClinicalTrials.gov
NAPO - Novel approach for oligospermia
NAPO is a single-center, sponsor-investigator-initiated, placebo-controlled, double-blinded randomized trial. Men with severe oligospermia were randomized in a 2:1 fashion to receive either denosumab 60 mg subcutaneously or a placebo. The primary outcome of the study is defined as the difference in sperm concentration (millions pr. mL) after one spermatogenesis cycle (80 days) after inclusion. Link to ClinicalTrials.gov
NT-NOA - Novel Treatment of Some Men with Non-Obstructive Azoospermia
NT-NOA is a single-center, sponsor-investigator-initiated intervention trial. Men with azoospermia. Subjects will receive denosumab 60 mg followed by a TESE (Testicular Sperm Extraction) after 90 days. The primary outcome of the study is defined as the occurence of spermatozoa in a semen sample (80 days) or during TESE (90 days) which will be compared to previous exams. Link to ClinicalTrials.gov
GRANULOMA : Hypercalcemia and Nephrolithiasis 
Today, there is an increased use of non-medical, invasive cosmetic treatments globally without sufficient awareness of possible health risks. A particular problem is young men injecting large amounts of paraffin oil into skeletal muscles especially on upper arms and chest to increase the visible size of the muscles. Several case reports have suggested that intramuscular injection of paraffin oil induces foreign body reaction and granuloma formation and subsequently hypercalcemia. Our hypothesis is that increased generation of activated vitamin D (1,25(OH)2D3) in the marcrophages may be responsible for the persistent hypercalcemia. Now the investigators want to include a large group of men who injected 100-10.000 ml paraffin oil to identify risk factors for developing hypercalcemia and try to understand the pathogenesis of the disease. Additionally, granuloma tissue from selected patients will be cultured ex vivo to investigate whether they produce 1,25(OH)2D3 or PTHrP and to test which drugs can most effectively be used to lower calcium levels in these men. Subsequently, we will try to stratify the men according to the severity of the changes in calcium homeostasis as we suggest that this stratification could be the basis for future intervention trials.
Link to ClinicalTrials.gov
Copenhagen Bone Gonadal Study
Today, it is evident that vitamin D (VD) has more widespread effects than the classical actions related to bone mineralization and calcium homeostasis1. VD deficiency results in impaired reproductive performance in various species of animals, and recently the investigators have shown that the VD receptor (VDR), activating (CYP2R1, CYP27A1, CYP27B1) and inactivating (CYP24A1) enzymes are expressed in the human testis, epididymis, seminal vesicle, prostate and spermatozoa. Our studies have showed that VD increases intracellular calcium in mature spermatozoa, and hence may be important not only for spermatogenesis but also for sperm maturation. A new, and yet unpublished cross sectional study of 300 young healthy Danish men showed that men with lower levels of serum VD have significantly lower number of normally developed and motile spermatozoa. Hitherto, most cases of male infertility have been classified as "idiopathic", and infertile couples have been referred to symptomatic treatment at infertility clinics. These fertility treatments are often physically demanding for the female partner as well as expensive for the health care system. Any treatment that might improve semen quality of involuntary infertile men would be beneficial both for the infertile couples and the society in general. Our findings that VD may play a role for human semen quality have not yet been tested clinically. However, if VD supplementation proves efficient this opens for the first time for a causal, safe and cheap treatment of at least some cases of "idiopathic" impaired semen quality. The investigators believe our new human data supported by the results from the VD deficient and VDR KO animal studies and the high proportion of VD deficient Danish men provide sufficient evidence to initiate a randomized clinical trial of VD supplementation to infertile men. Infertile men have also have unfavorable altered levels of sex hormones and higher mortality than fertile men. Since VD deficiency is associated with increased mortality, regulation of aromatase, immune system, bone metabolism, glucose metabolism, cardiovascular system etc. our suggested clinical trial may also be able to evaluate several secondary endpoints in addition to the potential effect on semen quality. Link to Cliniccal Trials.gov
Copenhagen First
To determine the significance of systemic RANKL inhibition for male reproduction, conducting a clinical controlled randomized double blinded intervention study on infertile men, to investigating whether Denosumab (Prolia) can increase semen quality and to investigate what subgroup of infertile men that might benefit from treatment. Link to ClinicalTrials.gov
TNFSF11 Inhibition and Fertility: a Prospective Study
The receptor activator of NF-kB ligand (RANKL) system is considered important for bone homeostasis and comprises three important factors. RANKL exist in three isoforms but the predominant function is mediated by the transmembrane ligand that binds to a specific receptor (receptor activator of NF-KB (RANK)) on a neighbour cell that subsequently activates NFKB and regulates cell cycle OPG is an endogenous secreted protein that binds RANKL and inhibits its signalling. Thus, the RANK/RANKL system is vital for activation of the bone resorbing cells (osteoclasts). In bone the bone synthesizing cells (osteoblasts) express RANKL that signals to RANK on the immature osteoclasts. This induces proliferation and activation of the cells they start to proliferate and resorp bone. OPG is produced by somatic cells in the bone and this production is regulated by sex hormones, TGF-B and various other substances. Today a human made recombinant antibody against RANKL, Denosumab is used to treat osteoporosis as it inhibits RANKL signalling and thus causes less bone resorption in humans. RANKL, RANK and OPG are expressed in the testis and this pathway appears to be a novel regulator of germ cell proliferation. Decreased semen quality is a major factor of male infertility. Semen quality is a measure of the ability of the sperm to accomplish fertilization. Evaluation of male fertility potential is today basically conducted through semen analysis. There is no treatment for men with no sperm in the ejaculate and there exist no drug that can increase sperm counts.Therefore, drugs that can lower RANKL expression/activity for instance an antibody against RANKL such as Denosumab may be used for this new indication: A new treatment option of infertile men with impaired semen quality.
Link to ClinicalTrials.gov
Clinical Tests to Predict the Success of Assisted Reproductive Techniques
Today, it is evident that vitamin D has more widespread effects than the classical actions related to bone mineralization and calcium homeostasis. Vitamin D deficiency results in impaired reproductive performance in various species of animals, and recently the investigators have shown that the Vitamin D receptor (VDR), activating (CYP2R1, CYP27A1, CYP27B1) and inactivating (CYP24A1) enzymes are expressed in the human testis, epididymis, seminal vesicle, prostate and spermatozoa. Functional studies showed that activated vitamin D increases intracellular calcium and sperm motility in mature spermatozoa, and hence may be important not only for spermatogenesis but also for sperm function. Any test that might assist in guiding the treatment of the infertile couple would be beneficial both for most infertile couples and the society in general. The fact that vitamin D may play a role for human semen quality are now being tested clinically. If vitamin D supplementation proves efficient this opens for the first time for a causal, safe and cheap treatment of at least some cases of "idiopathic" impaired semen quality. This may also have consequences in the in vitro setting as activated vitamin D may be used to select high quality sperm during assisted reproductive techniques. The presence of the vitamin D receptor and vitamin D metabolizing enzyme CYP24A1 in particular is able to discriminate spermatozoa from normal and infertile men. CYP24A1 is expressed at the annulus of normal sperm, but it is virtually absent from spermatozoa from infertile men. This indicates that CYP24A1 expression may assist in predicting the chance of success by using insemination (IUI), IVF or ICSI. CYP24A1 expression is induced by activated vitamin D, which indicates that other VDR activated genes also may serve as positive predictive markers of fertility. In addition, vitamin D metabolites and other factors in the female reproductive tract will be measured to determine if they alone or in combination with other markers can determine whether the best solution for the infertile couple would be to do IUI, IVF, or ICSI. The suggested clinical trial may therefore be able to evaluate several secondary endpoints in addition to CYP24A1 in our search for predictive markers for fertilization. For instance several biomarkers in serum, seminal plasma or follicular fluid in conjunction with genetic polymorphisms in several genes important for reproductive function. Link to ClinicalTrials.gov
Calciotropic Effects After HCG Stimulation Test
We have in a pilot study found that serum calcium levels change in response to hCG stimulation test. We observed that serum calcium level measured at baseline and 72 hours after hCG stimulation were different in men with gonadal insufficiency referred for this stimulation test. Now we want to investigate a large cohort of men referred for hCG stimulation test due to suspected impaired gonadal function. Link to ClinicalTrials.gov