- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02719093
Role of FSHR Polymorphism p.N680S in the Therapy With FSH in Patients Who Underwent Varicocele Surgery
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Two common SNPs (c.919 A>G, pT307A, rs 6165 and c.2039 A>G, p.N680S, rs6166) are located in linkage disequilibrium in exon 10 of FSHR. The 2039 A>G variant is regularly analyzed to characterize the exon 10 haplotype.
It is well known that follice-stimulating hormone (FSH) receptor (FSHR) polymorphism p.N680S mediates different responses to FSH in vitro, and this polymorphism is associated with the ovarian response in controlled ovarian hyperstimulation. In the last years, FSHR gene polymorphisms have been studied as potential risk factors for spermatogenetic failure. It is shown an influence of FSHR 2039 A>G on FSH levels and testicular volume. Trends of higher FSH and lower testicular volume were observed in G-allele carriers (Ala307/Ser680). Men homozygous for Thr307/Asn680 had a lower mean serum FSH concentration compared with men with other genotypes. In addition, sperm concentrations and the total sperm counts were higher and their testes volumes were larger. Another clinical study showed that the patients with heterozygous Thr/Ala + Asn/Ser combined genotype were 2.65 times more susceptible to infertility than the control group. It is also shown the higher sensitivity of the receptor in FSHR 2039 A>G AA homozygotes1-2. A recent Cochrane review showed a beneficial effect on live birth and pregnancy of gonadotrophin treatment for men with idiopathic male factor subfertility. These study suggest that the analysis of this gene represents a valid pharmacogenetic approach to the treatment of male infertility, confirming also the importance of strict criteria for the selection of patients to be treated with FSH. Which FSHR polymorphism can benefit from FSH treatment is clinically very important, in particular for what regards nonidiopathic patients. It is also relevant from a pharmacoeconomic point of view. In many andrological units, patients underwent adiuvant therapy with purified or recombinant FSH after varicocelectomy. FSH treatment in patients after varicocelectomy could improve spermatogenesis, but there aren't multicentric trials that confirm its validity. Usually, in our hospital only patients with a morphologic aspect of hypospermatogenesis underwent therapy with purified or recombinant FSH, because this therapy is not much useful in patient with Partial Sertoli-cell-only syndrome or maturation arrest. The purpose of our study is to correlate "non responder" patients who underwent FSH adiuvant therapy after varicocele surgery with a p.N680S FSHR polymorphism. Moreover the investigators suppose that "non responder" patients can beneficiate from a high-dose therapy with FSH.
This is a prospective intervention study in which are recruited males with OligoAstenoTeratozoospermic (OAT) and varicocele. The partecipants will undergo subinguinal microsurgical varicocelectomy (Marmar technique) and needle aspiration testicular cytology (Foresta technique). One-hundred patients with a morphologic aspect of hypospermatogenesis at testicular cytology will take recombinant follitropin alfa 150UI i.m. 3 times/week for at least three month. At 3th month the partecipants will have a semen analyses, without interrupting the treatment, and the FSHR gene polymorphism p.N680S characterization with PCR in high resolution melting HRM from DNA extracted by a simple blood sample. Patients who will have a significative increase in at least two parameters of semen, will be considered "responders" while patients in which semen parameters will not improve or worsen will be considered "non responders". "Responders" patients will interrupt their therapy and will have a new semen analyses at six month to verify the maintenance of their semen parameters after only three months of therapy. "Non responders" patients will take a daily dose of rFSH 150 UI for additional three months, because the investigators suppose that men with specific polymorphisms who don't response to therapy need an higher dose to stimulate spermatogenesis and to have a spontaneous pregnancy. At 6th month also these patients will have a new semen analyses in order to verify if there are some improvements in their spermatogenesis.
Study Type
Enrollment (Anticipated)
Phase
- Phase 4
Contacts and Locations
Study Contact
- Name: Maurizio Carrino
- Phone Number: +393347967341
- Email: cris63@libero.it
Study Contact Backup
- Name: Francesco Chiancone
- Phone Number: +393408639711
- Email: francescok86@gmail.com
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- OligoAstenoTeratozoospemic patient: Spermatozoa < 15 x 106/ml, Motility < 32%, <4% normal forms
Exclusion Criteria:
- Medications and psychoactive or anabolic drugs in last six months.
- Alcohol abuse in last three months.
- Systemic disease(liver cirrhosis, renal failure or others).
- Exposure to pelvic radiation, cytotoxic agent or exposure to environmental toxins.
- Testicular dysgenesis, cryptorchidism or genetic abnormalities (karyotype, Y-chromosome deletions)
- No trauma, testicular torsion, previous orchitis, previous testicular tumors, surgery that can compromise vascularisation of the testes and lead to testicular atrophy, cryptorchidism or genitourinary infection in last one year.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: recombinant FSH
recombinant FSH 150UI daily
|
Subcutaneous injection
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Total sperm count
Time Frame: After subinguinal microsurgical varicocelectomy and therapy with recombinant follitropin alfa 150UI i.m. 3 times/week for three months
|
Response to therapy indicated by significant increase in sperm count (million/ejaculate) according to WHO Laboratory Manual for the Examination and Processing of Human Semen (5th edn.)
|
After subinguinal microsurgical varicocelectomy and therapy with recombinant follitropin alfa 150UI i.m. 3 times/week for three months
|
Sperm concentration
Time Frame: After subinguinal microsurgical varicocelectomy and therapy with recombinant follitropin alfa 150UI i.m. 3 times/week for three months
|
Response to therapy indicated by significant increase in sperm concentration (million/mL) according to WHO Laboratory Manual for the Examination and Processing of Human Semen (5th edn.)
|
After subinguinal microsurgical varicocelectomy and therapy with recombinant follitropin alfa 150UI i.m. 3 times/week for three months
|
Total motility
Time Frame: After subinguinal microsurgical varicocelectomy and therapy with recombinant follitropin alfa 150UI i.m. 3 times/week for three months
|
Response to therapy indicated by significant increase in total motility (%) according to WHO Laboratory Manual for the Examination and
|
After subinguinal microsurgical varicocelectomy and therapy with recombinant follitropin alfa 150UI i.m. 3 times/week for three months
|
Progressive motility
Time Frame: After subinguinal microsurgical varicocelectomy and therapy with recombinant follitropin alfa 150UI i.m. 3 times/week for three months
|
Response to therapy indicated by significant increase in progressive motility (%) according to WHO Laboratory Manual for the Examination and
|
After subinguinal microsurgical varicocelectomy and therapy with recombinant follitropin alfa 150UI i.m. 3 times/week for three months
|
Sperm morphology (normal forms)
Time Frame: After subinguinal microsurgical varicocelectomy and therapy with recombinant follitropin alfa 150UI i.m. 3 times/week for three months
|
Response to therapy indicated by significant increase in sperm morphology (normal forms) (%) according to WHO Laboratory Manual for the Examination and
|
After subinguinal microsurgical varicocelectomy and therapy with recombinant follitropin alfa 150UI i.m. 3 times/week for three months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Total sperm count
Time Frame: After a daily dose of rFSH 150 UI for additional three months in "non responders" patients to the first three months of therapy with recombinant follitropin alfa 150UI i.m. 3 times/week
|
Response to therapy indicated by significant increase in sperm count (million/ejaculate) according to WHO Laboratory Manual for the Examination and
|
After a daily dose of rFSH 150 UI for additional three months in "non responders" patients to the first three months of therapy with recombinant follitropin alfa 150UI i.m. 3 times/week
|
Sperm concentration
Time Frame: After a daily dose of rFSH 150 UI for additional three months in "non responders" patients to the first three months of therapy with recombinant follitropin alfa 150UI i.m. 3 times/week
|
Response to therapy indicated by significant increase in sperm concentration (million/mL) according to WHO Laboratory Manual for the Examination and
|
After a daily dose of rFSH 150 UI for additional three months in "non responders" patients to the first three months of therapy with recombinant follitropin alfa 150UI i.m. 3 times/week
|
Total motility
Time Frame: After a daily dose of rFSH 150 UI for additional three months in "non responders" patients to the first three months of therapy with recombinant follitropin alfa 150UI i.m. 3 times/week
|
Response to therapy indicated by significant increase in total motility (%) according to WHO Laboratory Manual for the Examination and
|
After a daily dose of rFSH 150 UI for additional three months in "non responders" patients to the first three months of therapy with recombinant follitropin alfa 150UI i.m. 3 times/week
|
Progressive motility
Time Frame: After a daily dose of rFSH 150 UI for additional three months in "non responders" patients to the first three months of therapy with recombinant follitropin alfa 150UI i.m. 3 times/week
|
Response to therapy indicated by significant increase in progressive motility (%) according to WHO Laboratory Manual for the Examination and
|
After a daily dose of rFSH 150 UI for additional three months in "non responders" patients to the first three months of therapy with recombinant follitropin alfa 150UI i.m. 3 times/week
|
Sperm morphology (normal forms)
Time Frame: After a daily dose of rFSH 150 UI for additional three months in "non responders" patients to the first three months of therapy with recombinant follitropin alfa 150UI i.m. 3 times/week
|
Response to therapy indicated by significant increase in sperm morphology (normal forms) (%) according to WHO Laboratory Manual for the Examination and
|
After a daily dose of rFSH 150 UI for additional three months in "non responders" patients to the first three months of therapy with recombinant follitropin alfa 150UI i.m. 3 times/week
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Director: Maurizio Carrino, AORN A.CARDARELLI
Publications and helpful links
General Publications
- Tuttelmann F, Laan M, Grigorova M, Punab M, Sober S, Gromoll J. Combined effects of the variants FSHB -211G>T and FSHR 2039A>G on male reproductive parameters. J Clin Endocrinol Metab. 2012 Oct;97(10):3639-47. doi: 10.1210/jc.2012-1761. Epub 2012 Jul 12.
- Casarini L, Moriondo V, Marino M, Adversi F, Capodanno F, Grisolia C, La Marca A, La Sala GB, Simoni M. FSHR polymorphism p.N680S mediates different responses to FSH in vitro. Mol Cell Endocrinol. 2014 Aug 5;393(1-2):83-91. doi: 10.1016/j.mce.2014.06.013. Epub 2014 Jun 23.
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- CHIRURGIAANDROLOGICA-1
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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