Clinical Trial to Assess the Effect of Testosterone in Patients With Poor Ovarian Response (TESTOPRIM)
NCT ID: NCT03378713
Last Updated: 2019-08-13
Study Results
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Basic Information
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COMPLETED
PHASE3
63 participants
INTERVENTIONAL
2017-08-07
2019-02-11
Brief Summary
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Detailed Description
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Regarding the duration of treatment, the investigators decided to include two groups of testosterone treatment (compared to the control group) with different duration. One will explore the role of testosterone in prolonged treatments (two full menstrual cycles). The other will test the pattern most commonly used in most studies, that is, testosterone in luteal phase of the previous cycle (about 10 days in short protocol with GnRH antagonist). In this way the investigators will establish an absolute comparison with the control group and relative between both treatment groups (long testosterone vs. short testosterone) to determine if / which of the two regimen (the two, only one or none) improves the number of mature oocytes recovered.
The product under investigation is testosterone gel, transdermal administration, 50 mg / single dose (Testim®, Ferring, Madrid, Spain). Regarding the dose, the investigators decided to keep the most used in the rest of studies (12.5 mg / day).
This study population will include only patients diagnosed with POR based on ESHRE Bologna criteria, in order to homogenize the population and allow comparisons with other studies in the future.
Regarding the dose, the investigators decided to keep the most used in the rest of studies (12.5 mg/day) which so far has been the only one proven effective. It is clearly possible that lower and more physiological doses are equally effective, but this yet has to be proven in well-designed studies. The gel is self-administered by the patients who are adequately instructed by a research nurse.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
SINGLE
Study Groups
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GROUP 1: Long testosterone
Application of testosterone in transdermal gel during the 2 cycles prior to initiation of controlled ovarian stimulation and until the onset of second menstruation (approximately 56 days). The COS begins the day after the last testosterone application.
GROUP 1: Long testosterone
Application of testosterone in transdermal gel during the 2 cycles prior to initiation of controlled ovarian stimulation and until the onset of second menstruation (approximately 56 days). The COS begins the day after the last testosterone application
GROUP 2: Short testosterone
Application of testosterone in transdermal gel begins on day 21 of menstrual cycle, from the luteal phase of the cycle prior to initiation of controlled ovarian stimulation and until menstruation (approximately 10 days). The COS begins the day after the last testosterone application.
GROUP 2: Short testosterone
Application of testosterone in transdermal gel begins on day 21 of menstrual cycle, from the luteal phase of the cycle prior to initiation of controlled ovarian stimulation and until menstruation (approximately 10 days). The COS begins the day after the last testosterone application.
GROUP 3: Control
The COS starts directly on the second day of the cycle without prior medication.
GROUP 3: Control
The COS starts directly on the second day of the cycle without prior medication.
Interventions
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GROUP 1: Long testosterone
Application of testosterone in transdermal gel during the 2 cycles prior to initiation of controlled ovarian stimulation and until the onset of second menstruation (approximately 56 days). The COS begins the day after the last testosterone application
GROUP 2: Short testosterone
Application of testosterone in transdermal gel begins on day 21 of menstrual cycle, from the luteal phase of the cycle prior to initiation of controlled ovarian stimulation and until menstruation (approximately 10 days). The COS begins the day after the last testosterone application.
GROUP 3: Control
The COS starts directly on the second day of the cycle without prior medication.
Eligibility Criteria
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Inclusion Criteria
* Female older than 18 years old at the time of randomization.
* Prior diagnosis of poor ovarian response (POR) according to ESHRE Bologna criteria. Patients must meet at least 2 of the following:
* Advanced maternal age (40 years or more) or any other risk factor for POR.
* A previous POR (3 oocytes or less) with a conventional ovarian stimulation protocol.
* Abnormal ovarian reserve test (RFA \<5-7 or AMH 3.3-7.9 pmol / l).
Exclusion Criteria
* Presence of uterine pathology defined as submucous myomas or endometrial polyps, documented by transvaginal ultrasound.
* Couples with severe male factor defined as REM \<1 or azoospermia.
* Hydrosalpinx unilateral or bilateral uncorrected.
* Perimenopausal patients with irregular menstrual cycles.
* Concurrent untreated endocrine disorders.
* Patients who have participated in a clinical trial in a period of less than one month.
* Known allergy to the drug.
* Patients who have received androgen treatment within 3 months prior to inclusion in the study.
* BMI\> 35 kg / m2
18 Years
FEMALE
No
Sponsors
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Instituto de Investigacion Sanitaria La Fe
OTHER
Responsible Party
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Principal Investigators
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Jessica Subirá
Role: PRINCIPAL_INVESTIGATOR
Hospital Universitari i Politècnic La Fe, Valencia, Spain
Locations
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Hospital Universitario y Politécnico La Fe
Valencia, , Spain
Countries
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References
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Tarlatzis BC, Zepiridis L, Grimbizis G, Bontis J. Clinical management of low ovarian response to stimulation for IVF: a systematic review. Hum Reprod Update. 2003 Jan-Feb;9(1):61-76. doi: 10.1093/humupd/dmg007.
Gorgy A, Naumann N, Bates S, Craft IL. Assisted conception following poor ovarian response to gonadotrophin stimulation. Br J Obstet Gynaecol. 1997 Dec;104(12):1420-1. doi: 10.1111/j.1471-0528.1997.tb11020.x. No abstract available.
Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L; ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011 Jul;26(7):1616-24. doi: 10.1093/humrep/der092. Epub 2011 Apr 19.
Kyrou D, Kolibianakis EM, Venetis CA, Papanikolaou EG, Bontis J, Tarlatzis BC. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil Steril. 2009 Mar;91(3):749-66. doi: 10.1016/j.fertnstert.2007.12.077. Epub 2008 Jul 21.
Pandian Z, McTavish AR, Aucott L, Hamilton MP, Bhattacharya S. Interventions for 'poor responders' to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF). Cochrane Database Syst Rev. 2010 Jan 20;(1):CD004379. doi: 10.1002/14651858.CD004379.pub3.
Jeve YB, Bhandari HM. Effective treatment protocol for poor ovarian response: A systematic review and meta-analysis. J Hum Reprod Sci. 2016 Apr-Jun;9(2):70-81. doi: 10.4103/0974-1208.183515.
Bastu E, Buyru F, Ozsurmeli M, Demiral I, Dogan M, Yeh J. A randomized, single-blind, prospective trial comparing three different gonadotropin doses with or without addition of letrozole during ovulation stimulation in patients with poor ovarian response. Eur J Obstet Gynecol Reprod Biol. 2016 Aug;203:30-4. doi: 10.1016/j.ejogrb.2016.05.027. Epub 2016 May 24.
Ertzeid G, Storeng R. The impact of ovarian stimulation on implantation and fetal development in mice. Hum Reprod. 2001 Feb;16(2):221-5. doi: 10.1093/humrep/16.2.221.
Van der Auwera I, D'Hooghe T. Superovulation of female mice delays embryonic and fetal development. Hum Reprod. 2001 Jun;16(6):1237-43. doi: 10.1093/humrep/16.6.1237.
Baker VL, Brown MB, Luke B, Smith GW, Ireland JJ. Gonadotropin dose is negatively correlated with live birth rate: analysis of more than 650,000 assisted reproductive technology cycles. Fertil Steril. 2015 Nov;104(5):1145-52.e1-5. doi: 10.1016/j.fertnstert.2015.07.1151. Epub 2015 Aug 18.
Escriva AM, Diaz-Garcia C, Monterde M, Rubio JM, Pellicer A. Antral Follicle Priming Before Intracytoplasmic Sperm Injection in Previously Diagnosed Low Responders: A Randomized Controlled Trial (FOLLPRIM). J Clin Endocrinol Metab. 2015 Jul;100(7):2597-605. doi: 10.1210/jc.2015-1194. Epub 2015 May 8.
Fanchin R, Cunha-Filho JS, Schonauer LM, Kadoch IJ, Cohen-Bacri P, Frydman R. Coordination of early antral follicles by luteal estradiol administration provides a basis for alternative controlled ovarian hyperstimulation regimens. Fertil Steril. 2003 Feb;79(2):316-21. doi: 10.1016/s0015-0282(02)04574-0.
Bosdou JK, Venetis CA, Kolibianakis EM, Toulis KA, Goulis DG, Zepiridis L, Tarlatzis BC. The use of androgens or androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update. 2012 Mar-Apr;18(2):127-45. doi: 10.1093/humupd/dmr051. Epub 2012 Feb 3.
Massin N, Cedrin-Durnerin I, Coussieu C, Galey-Fontaine J, Wolf JP, Hugues JN. Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique--a prospective, randomized, double-blind study. Hum Reprod. 2006 May;21(5):1204-11. doi: 10.1093/humrep/dei481. Epub 2006 Feb 13.
Balasch J, Fabregues F, Penarrubia J, Carmona F, Casamitjana R, Creus M, Manau D, Casals G, Vanrell JA. Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH. Hum Reprod. 2006 Jul;21(7):1884-93. doi: 10.1093/humrep/del052. Epub 2006 Mar 3.
Fabregues F, Penarrubia J, Creus M, Manau D, Casals G, Carmona F, Balasch J. Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial. Hum Reprod. 2009 Feb;24(2):349-59. doi: 10.1093/humrep/den428. Epub 2008 Dec 3.
Kim CH, Howles CM, Lee HA. The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders. Fertil Steril. 2011 Feb;95(2):679-83. doi: 10.1016/j.fertnstert.2010.07.1077.
Kim CH, Ahn JW, Moon JW, Kim SH, Chae HD, Kang BM. Ovarian Features after 2 Weeks, 3 Weeks and 4 Weeks Transdermal Testosterone Gel Treatment and Their Associated Effect on IVF Outcomes in Poor Responders. Dev Reprod. 2014 Sep;18(3):145-52. doi: 10.12717/DR.2014.18.3.145.
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Vendola KA, Zhou J, Adesanya OO, Weil SJ, Bondy CA. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest. 1998 Jun 15;101(12):2622-9. doi: 10.1172/JCI2081.
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Sen A, Hammes SR. Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. Mol Endocrinol. 2010 Jul;24(7):1393-403. doi: 10.1210/me.2010-0006. Epub 2010 May 25.
Nielsen ME, Rasmussen IA, Kristensen SG, Christensen ST, Mollgard K, Wreford Andersen E, Byskov AG, Yding Andersen C. In human granulosa cells from small antral follicles, androgen receptor mRNA and androgen levels in follicular fluid correlate with FSH receptor mRNA. Mol Hum Reprod. 2011 Jan;17(1):63-70. doi: 10.1093/molehr/gaq073. Epub 2010 Sep 14.
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Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. 2011 Jul;26(7):1768-74. doi: 10.1093/humrep/der106. Epub 2011 May 10.
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Other Identifiers
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TESTOPRIM
Identifier Type: -
Identifier Source: org_study_id
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