Role of FSHR Polymorphism p.N680S in the Therapy With FSH in Patients Who Underwent Varicocele Surgery

March 20, 2016 updated by: Maurizio Carrino, U.O. Chirurgia Andrologica
Two common SNPs are located in linkage disequilibrium in exon 10 of FSHR. The 2039 A>G variant is regularly analyzed to characterize the exon 10 haplotype. In the last years, it has been showed an influence of FSHR 2039 A>G on FSH levels, testicular volume, sperm concentration and the total sperm count. A recent Cochrane review showed a beneficial effect on live birth and pregnancy of gonadotrophin treatment for men with idiopathic male factor subfertility. Which FSHR polymorphism can benefit from FSH treatment is clinically very important, in particular for what regards nonidiopathic patients. 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).

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
100

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

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Study Contact

Study Contact

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Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 35 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: recombinant FSH
recombinant FSH 150UI daily
Drug: recombinant FSH
Subcutaneous injection
Other Names:
  • Puregon
  • Gonal-F

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
U.O. Chirurgia Andrologica

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Androcenter, Napoli, Italy

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Maurizio Carrino, AORN A.CARDARELLI

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

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Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 1, 2016

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 1, 2017

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2017

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 12, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 20, 2016

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 25, 2016

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 25, 2016

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 20, 2016

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CHIRURGIAANDROLOGICA-1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

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