Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia

NCT02605070 | Terminated Phase 3

• 1 other identifier: FSH_IMEN
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Single center, prospective, open clinical study to determine the genomic imprint (epigenetic modification) in a series of male infertility patients with alterations in their spermiogram (oligozoospermia) compared to a group of fertile patients in order to evaluate the effect of FSH ( follicle stimulating hormone) administration on these modifications and on male infertility.

Conditions

Male Infertility

Outcome Measures

Primary Outcomes (1)

• Epigenetic modification

  To determine the genomic imprint (epigenetic modification) in a series of male infertility patients with alterations in their spermiogram (oligozoospermia) compared to a group of fertile patients in order to evaluate the effect of FSH administration on these modifications and on male infertility

  12 weeks after treatment.

Secondary Outcomes (3)

• To assess the main characteristics of the spermiograms of infertility patients before and after FSH treatment.

  First week and end of treatment visit (12 weeks).

• To assess modifications in the hormones involved in sperm formation in infertility patients before and after treatment.

  First week and end of treatment visit (12 weeks)

• Pregnancy rate.

  6-7 weeks after transfer of the embryo.

Study Arms (2)

Infertility group

EXPERIMENTAL

Patients referred will be evaluated to participate in the study and then asked to take part.In this visit,the normal protocol for infertility patients will be followed and at least 2 spermiograms and a blood test analyzing the following parameters:FSH, LH,Estradiol,Total testosterone,SHBG, Albumin,Calculation of bioavailable testosterone,Prolactin.If these tests have not been performed,a second baseline visit will be scheduled.Should the patient meet all the inclusion criteria and after the patient has signed an informed consent form agreeing to participate in the study,the physician will prescribe the medication and schedule visits.Before initiating the treatment, they will provide a semen sample.This sample will be sent to the Center for Reproductive Biology,where the sample will be subjected to epigenetic analysis.The patient will be given samples of Bravelle.It is administered subcutaneously.The dose will be 150 IU 3times a week for 3months

Drug: Bravelle

Fertily group

NO INTERVENTION

Patients who volunteer will be informed of the nature of the study and asked to sign the informed consent form. At least two spermiograms will be performed along with a blood test analyzing the following parameters:FSH,LH,Estradiol,Total testosterone,SHBG,Albumin,Estimation of bioavailable testosterone,Prolactin. A second baseline visit will be scheduled to evaluate the test results and to check whether these subjects meet all the inclusion criteria for the control group. Those subjects will provide a semen sample which will be stored at -20º C. Outpatient visit: week twelve: a physical exam will be carried out to identify any adverse reactions. A blood test and a semen sample will also be obtained.

Interventions

Bravelle DRUG

Bravelle will be provided to all patients in the treatment group by the principal investigator (PI) or another member of the research team. From week nine on, the patients will undergo a physical examination on three different occasions to assess the appearance of any adverse reactions during treatment. It will be up to the patient to communicate the appearance of signs or symptoms which could be associated with the use of the drug. At week 12 the patient will be scheduled for another visit to perform a semen study and to measure new hormone levels. To this end, a blood test will be carried out (FSH, LH, estradiol, total testosterone, SHBG, and albumin to calculate the amount of bioavailable testosterone). A semen sample will also be obtained to carry out a spermiogram according to WHO guidelines; part of this sample will be used for epigenetic analysis.

Infertility group

Eligibility Criteria

• Age: 25 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Between 25-45 years of age.
• Total sperm concentration (concentration in millions/mL x volume in mL) between 1-10 million (oligozoospermia) in at least 2 spermiograms obtained after a 2-4 day period of sexual abstinence and with a 7-day separation period between tests.
• Caucasian.
• Inability of the couple to become pregnant after one year of sexual relations without using any type of contraception.
• FSH 2-12 IU/mL.
• Total testosterone \>300 ng/mL and bioavailable testosterone (calculated with the Sexual Hormone Binding Globulin or SHBG albumin) \>145 ng/dL.
• Between 25-45 years of age.
• Caucasian.
• Sperm concentration and motility above the 5th percentile according to the parameters set forth in the 5th edition of the World Health Organization (WHO) guidelines in at least two spermiograms obtained after a 2-4 day period of sexual abstinence and with a 7-day period between tests.
• Seminal volume \>1 mL.
• Estradiol \<50 pg/mL
• FSH \<4.5 IU/L.
• Total testosterone \>300 ng/dL and bioavailable testosterone \>145 ng/dL.
• No vasectomy.
• Has sired a child within the past 5 years.

You may not qualify if:

• Total sperm concentration \<1 million.
• Sperm motility of 0%.
• History of cryptorchidism, malignant or benign tumors, known chromosomal abnormalities, testicular tor- sion, testicular trauma, orchitis.
• Drug use in the past 120 days. thyroid dysfunction
• Medical history:thyroid dysfunction, blood disease, diabetes.
• Use of anabolic steroids in the past 2 years or for more than 2 years.
• Body mass index \>30 kg/m .
• Intake of over 21 units of alcohol/week in the past 120 days.

Sponsors & Collaborators

• Instituto de Investigacion Sanitaria La Fe: lead

Study Sites (1)

Hospital Universitari i Politècnic La Fe

Valencia, 46026, Spain

Location

Related Publications (12)

• Boivin J, Bunting L, Collins JA, Nygren KG. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod. 2007 Jun;22(6):1506-12. doi: 10.1093/humrep/dem046. Epub 2007 Mar 21.

  PMID: 17376819 RESULT

• Dohle GR, Halley DJ, Van Hemel JO, van den Ouwel AM, Pieters MH, Weber RF, Govaerts LC. Genetic risk factors in infertile men with severe oligozoospermia and azoospermia. Hum Reprod. 2002 Jan;17(1):13-6. doi: 10.1093/humrep/17.1.13.

  PMID: 11756355 RESULT

• Simoni M, Gromoll J, Dworniczak B, Rolf C, Abshagen K, Kamischke A, Carani C, Meschede D, Behre HM, Horst J, Nieschlag E. Screening for deletions of the Y chromosome involving the DAZ (Deleted in AZoospermia) gene in azoospermia and severe oligozoospermia. Fertil Steril. 1997 Mar;67(3):542-7. doi: 10.1016/s0015-0282(97)80083-0.

  PMID: 9091344 RESULT

• Gianotten J, Lombardi MP, Zwinderman AH, Lilford RJ, van der Veen F. Idiopathic impaired spermatogenesis: genetic epidemiology is unlikely to provide a short-cut to better understanding. Hum Reprod Update. 2004 Nov-Dec;10(6):533-9. doi: 10.1093/humupd/dmh045. Epub 2004 Oct 1.

  PMID: 15465836 RESULT

• Jenkins TG, Carrell DT. Dynamic alterations in the paternal epigenetic landscape following fertilization. Front Genet. 2012 Jul 31;3:143. doi: 10.3389/fgene.2012.00143. eCollection 2012.

  PMID: 23024648 RESULT

• Kelly TL, Li E, Trasler JM. 5-aza-2'-deoxycytidine induces alterations in murine spermatogenesis and pregnancy outcome. J Androl. 2003 Nov-Dec;24(6):822-30. doi: 10.1002/j.1939-4640.2003.tb03133.x.

  PMID: 14581508 RESULT

• Houshdaran S, Cortessis VK, Siegmund K, Yang A, Laird PW, Sokol RZ. Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm. PLoS One. 2007 Dec 12;2(12):e1289. doi: 10.1371/journal.pone.0001289.

  PMID: 18074014 RESULT

• Kobayashi H, Sato A, Otsu E, Hiura H, Tomatsu C, Utsunomiya T, Sasaki H, Yaegashi N, Arima T. Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients. Hum Mol Genet. 2007 Nov 1;16(21):2542-51. doi: 10.1093/hmg/ddm187. Epub 2007 Jul 17.

  PMID: 17636251 RESULT

• Benchaib M, Braun V, Ressnikof D, Lornage J, Durand P, Niveleau A, Guerin JF. Influence of global sperm DNA methylation on IVF results. Hum Reprod. 2005 Mar;20(3):768-73. doi: 10.1093/humrep/deh684. Epub 2005 Jan 7.

  PMID: 15640258 RESULT

• Reyes-Fuentes A, Chavarria ME, Carrera A, Aguilera G, Rosado A, Samojlik E, Iranmanesh A, Veldhuis JD. Alterations in pulsatile luteinizing hormone and follicle-stimulating hormone secretion in idiopathic oligoasthenospermic men: assessment by deconvolution analysis--a clinical research center study. J Clin Endocrinol Metab. 1996 Feb;81(2):524-9. doi: 10.1210/jcem.81.2.8636262.

  PMID: 8636262 RESULT

• Fujisawa M, Kanzaki M, Hayashi A, Tanaka H, Okada H, Arakawa S, Kamidono S. Alteration of the hypothalamus-pituitary-testis axis in oligozoospermic men with normal gonadotropin levels. Int J Urol. 1995 Sep;2(4):273-6. doi: 10.1111/j.1442-2042.1995.tb00471.x.

  PMID: 8564748 RESULT

• Boissonnas CC, Jouannet P, Jammes H. Epigenetic disorders and male subfertility. Fertil Steril. 2013 Mar 1;99(3):624-31. doi: 10.1016/j.fertnstert.2013.01.124.

  PMID: 23714437 RESULT

MeSH Terms

Conditions

Infertility, Male

Interventions

Urofollitropin

Condition Hierarchy (Ancestors)

Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Infertility; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Menotropins; Gonadotropins, Pituitary; Gonadotropins; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormones, Anterior; Pituitary Hormones; Peptides; Amino Acids, Peptides, and Proteins

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2015
• First Posted: November 16, 2015
• Study Start: November 1, 2015
• Primary Completion: June 13, 2017
• Study Completion: June 13, 2017
• Last Updated: March 2, 2018

Record last verified: 2017-05

Locations

ES (1)