NT-NOA - Novel Treatment of Some Men With Non-Obstructive Azoospermia

This clinical interventional study aims to assess whether treatment with denosumab in combination with letrozole can improve sperm production in infertile men with non-obstructive azoospermia selected by serum anti-mullerian hormone (AMH) as a positive predictive biomarker.

Infertility is a health issue worldwide with more than 15% of couples experiencing infertility. Male factors contribute in 50% of all cases and is the sole cause in 30% of all infertile couples . Treatment options for the male infertility are limited and only specific conditions like varicocele and hypogonadotropic hypogonadism can be effectively treated with surgery and hormonal stimulation, respectively. However, for the remaining 90% of infertile men, no treatment options exist. Instead, their female partners must undergo fertility treatment. Men with the most pronounced impairment of semen quality, men with azoospermia, have no sperm in the ejaculate and are classically divided into obstructive azoospermia (OA) and non-obstructive azoospermia (NOA), with the ladder being the most common. These men needs to have surgery performed for sperm retrieval with either testicular sperm aspiration (TESA), testicular sperm extraction (TESE) or micro testicular sperm extraction (microTESE) in order to have a chance of becoming biological fathers. The chance of successful sperm retrieval in men with OA is close to 100%, whereas men with NOA have a significantly lower chance with only around 10-40% being successful. This is due to the vast difference in etiology between men with OA and NOA. Even with a successful surgical intervention only half of the cases will result in a live birth, leaving the majority of men with NOA no chance of becoming biological fathers. Therefore, novel treatment options for even a minor sub-group of these men are warranted. RANKL is a ligand for the receptor activator of nuclear factor kappa beta (RANK), and their pathway plays a prominent role in the regulation of bone metabolism. The binding of RANKL to RANK on osteoclast precursors induces osteoclast maturation and activation, thereby stimulating bone resorption, and regulates cell cycle i.e., proliferation, differentiation, and apoptosis. Osteoprotegerin (OPG) is a secreted decoy receptor that controls RANKL-RANK interaction by binding RANKL and inhibits activation of RANK and preventing osteoclast differentiation and activation. Denosumab, a drug used in millions of patients worldwide under trade names Prolia® and Xgeva®, inhibits the RANKL pathway and is used to treat osteoporosis and bone metastases. The drug's mechanism of action inhibits RANKL and thus inhibits bone resorption through reduced osteoclast activation. This reduces the loss of bone mineral density (BMD), which reduces the risk of bone loss and thereby the risk of fracture and osteoporosis. Denosumab has been shown in several clinical studies to be a safe and effective drug in both women and men and has been in clinical use in both sexes for many years. As Denosumab has a teratogenic effect, pharmacokinetic studies in both monkeys and healthy men were performed before approval of the drug as a treatment for osteoporosis in men. These studies showed that Denosumab concentration in semen does not pose a ris Покажи пълното описание...

Inclusion Criteria: * Infertile men ≥ 18 years and \< 60 years of age with azoospermia with normal semen volume (\> 0.9 mL) verified by minimum 2 semen samples. * No identifiable cause of obstruction. * Testis size (Prader Orchidometer) ≤ 15 mL on both sides in patients where no prior TESE is available * Serum AMH levels ≥5 pmol/L. Exclusion Criteria: * Chronic diseases, defined as diagnosis where signs, symptoms, and treatment imply an expected long duration and lack of a cure, such as diabetes mellitus, metabolism disorders, osteoporosis, colitis, etc. * Chromosome anomalies e.g. Klinefelter Syndrome, XX male * AZFa/b/c microdeletions besides b2/b3 og gr/gr * Detected CFTR mutation * Men with current or previous malignancies, or at potential risk of testicular cancer after baseline examination and ultrasound will be excluded * Men with hypocalcemia at baseline, defined as albumin corrected calcium \< 2.17 mmol/L or total calcium \< 2.14 mmol/L * Serum vitamin D (25OHD) levels \< 25 nmol/L * estimated Glomerular Filtration Rate (eGFR) \< 60 mL/min/1,73 m2 * Insufficient dental status * Hypersensitivity to latex, Denosumab, or to any of the excipients (acetic acid, sodium hydroxide, Sorbitol (E420), Polysorbate 20) will be excluded. * Serum Inhibin B \< 5 pg/mL * Androgen replacement therapy * Hypogonadotropic hypogonadism * BMI ≥ 35 kg/m2