Infertility Clinical Trial
Official title:
Denosumab and Male Infertility: a Prospective Intervention Study
Verified date | March 2019 |
Source | Rigshospitalet, Denmark |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 12 |
Est. completion date | January 2019 |
Est. primary completion date | February 2017 |
Accepts healthy volunteers | No |
Gender | Male |
Age group | 18 Years to 65 Years |
Eligibility |
Infertile men referred for evaluation of male infertility at department of growth and
reproduction or infertile men interested in participation in clinical trials. Inclusion Criteria: - Male with an age > 18 years old - Referred for male infertility with sperm concentration >= 0.1 million/ml. - Additionally, all men must have either sperm concentration < 20 million/ml or < 50% progressive motile spermatozoa or < 12% morphological normal spermatozoa using strict criteria Exclusion Criteria: Men with chronic diseases such as - diabetes mellitus - Thyroid disease - endocrine disturbances in need of treatment - malignant disease - or diseases known to interfere with calcium homeostasis (such as inflammatory disease with granuloma: sarcoidoses, tuberculosis, Wegeners, vasculitis, inflammatory bowel disease (Crohn's and colitis ulcerosa etc). - Men with previous testis cancer - If there is an indication for testis biopsy and it is planned or conducted within the next 6 months - Serum 25-hydroxy-D3 < 50 nmol/l - Serum Calcium ion < 1,18 or > 1,35 mmol/l - Serum OPG >4 pg/ml - Serum PTH <1.6 or >6 pmol/l - Inhibin-B < 50 pg/ml - Latex Allergy - no good oral condition or major implants - BMD < -1,5 in columna lumbalis and collum femoris Criteria for drop out: - Abrogation of the treatment - Newly diagnosed endocrine, calcium metabolic disease, parathyroid, thyroid, diabetes or other endocrine disease in need of treatment - New malignant disease - Treatment with chemotherapy, immunomodulating therapy, salazopyrin - Oral or iv treatment with steroid hormones - New treatment with diuretics, antihypertensive treatment, treatment the heart, calcium channel blockers - If testis biopsy is performed or other surgery in the genital region during the trial - Prolia Intoxication |
Country | Name | City | State |
---|---|---|---|
Denmark | Rigshospitalet | Copenhagen |
Lead Sponsor | Collaborator |
---|---|
Martin Blomberg Jensen |
Denmark,
Anastasilakis AD, Toulis KA, Goulis DG, Polyzos SA, Delaroudis S, Giomisi A, Terpos E. Efficacy and safety of denosumab in postmenopausal women with osteopenia or osteoporosis: a systematic review and a meta-analysis. Horm Metab Res. 2009 Oct;41(10):721-9. doi: 10.1055/s-0029-1224109. Epub 2009 Jun 17. Review. — View Citation
Anastasilakis AD, Toulis KA, Polyzos SA, Terpos E. RANKL inhibition for the management of patients with benign metabolic bone disorders. Expert Opin Investig Drugs. 2009 Aug;18(8):1085-102. doi: 10.1517/13543780903048929. Review. — View Citation
Anastasilakis, A. D., et al.
Blomberg, Jensen M.
Boonen, S., et al.
Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11. Erratum in: N Engl J Med. 2009 Nov 5;361(19):1914. — View Citation
Jorgensen, A., et al.
Kwiecinski GG, Petrie GI, DeLuca HF. Vitamin D is necessary for reproductive functions of the male rat. J Nutr. 1989 May;119(5):741-4. — View Citation
one, H. G., et al.
Papapoulos, S., et al.
Polyzos, S. A., et al.
Schwarz, P., et al.
Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001 May;16(5):972-8. Review. — View Citation
Toulis KA, Anastasilakis AD. Increased risk of serious infections in women with osteopenia or osteoporosis treated with denosumab. Osteoporos Int. 2010 Nov;21(11):1963-4. doi: 10.1007/s00198-009-1145-1. Epub 2009 Dec 15. Erratum in: Osteoporos Int. 2010 Nov;21(11):1965. A Toulis, K [corrected to Toulis, K A]; D Anastasilakis, A [corrected to Anastasilakis, A D]. — View Citation
Uhland AM, Kwiecinski GG, DeLuca HF. Normalization of serum calcium restores fertility in vitamin D-deficient male rats. J Nutr. 1992 Jun;122(6):1338-44. — View Citation
* Note: There are 15 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Change in sperm production | evaluated by determining total sperm count and sperm concentration | after 5, 20, 40, 80, 120, 180 days | |
Secondary | change in sperm DNA fragmentation index | DNA fragmentation | after 20 and 120 days | |
Secondary | change in number of motile sperm | multiplying the percentage of motile sperm with total sperm count and similar for progressive motile sperm | after 5, 20, 40, 80, 120, 180 days | |
Secondary | change in number of morphological normal sperm | multiplying the percentage of morphological normal sperm with total sperm count | after 5, 20, 40, 80, 120, 180 days | |
Secondary | change in sperm motility | motilility (ABC) and progressive motility (AB) | after 5, 20, 40, 80, 120, 180 days | |
Secondary | change in semen morphology | morphology | after 5, 20, 40, 80, 120, 180 days | |
Secondary | change in semen volume | volume | after 5, 20, 40, 80, 120, 180 days | |
Secondary | change in Inhibin B | Change in inhibin B, Inhibin B/FSH ratio | after 5, 20, 40, 80, 120, 180 days | |
Secondary | change in sex hormones or gonadotropins | testosterone, estradiol, INSL3, AMH, progesterone, LH, FSH | after 5, 20, 40, 80, 120, 180 days | |
Secondary | change in BMD | lumbar spine and collum femoris | after180 days | |
Secondary | Change in vitamin d metabolites | 25-OHD, 1,25OHD, 24,25OHD, | after 5, 20, 40, 80, 120, 180 days | |
Secondary | change in seminal plasma concentrations of RANKL, OPG, RANK | after 5, 20, 40, 80, 120, 180 days | ||
Secondary | change i serum PTH, alkaline phosphatase, calcium, phosphate, | after 5, 20, 40, 80, 120, 180 days | ||
Secondary | change i serum FGF23, Klotho, osteocalcin, osteopontin, calcitonin, pnp, procollagen III, OPG, RANKL, Sclerostin and other bone markers | after 5, 20, 40, 80, 120, 180 days | ||
Secondary | change in the number of spermatozoa expressing CYP24A1, VDR or RANKL | after 5, 20, 40, 80, 120, 180 days | ||
Secondary | change in seminal plasma levels of pH,HCO3, calcium, zink, phosphat, FGF23, Klotho, osteocalcin, osteopontin. | after 5, 20, 40, 80, 120, 180 days | ||
Secondary | change in seminal plasma levels of FGF23, Klotho, osteocalcin, osteopontin. | after 5, 20, 40, 80, 120, 180 days | ||
Secondary | change in bloodpressure. | after 180 days |
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