Testosterone TRANSdermal Gel for Poor Ovarian Responders Trial

Condition(s) targeted: Infertility; Poor Ovarian Response

Intervention: Testosterone gel (Drug); Placebo gel (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Universitair Ziekenhuis Brussel

Official(s) and/or principal investigator(s):
Nikolaos P Polyzos, MD PhD, Principal Investigator, Affiliation: Universitair Ziekenhuis Brussel

Overall contact:
Nikolaos P Polyzos, MD PhD, Phone: 003224749087, Email: n.polyzos@gmail.com

Previous work indicates that 2 months androgen pre-treatment may equip preantral follicles with more FSH receptors and increase the cohort of follicles surviving to the recruitable antral stage. In this regard it may result in an increase in the oocyte yield and the reproductive outcome in women with poor ovarian response. These findings provide a strong rationale for a definitive large RCT. The TTRANSPORT study will include 400 women with poor ovarian response randomized to receive pre-treatment with transdermal testosterone gel or placebo in order to provide conclusive evidence regarding the superiority or not of transdermal testosterone pre-treatment for the management of poor ovarian responders fulfilling the Bologna criteria.

Official title: Transdermal Testosterone Gel for Poor Ovarian Responders. A Multicenter Double-blind Placebo Controlled Randomized Trial

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Clinical pregnancy

Secondary outcome:

Ongoing pregnancy

Biochemical pregnancy

Number of oocytes retrieved

Number of MII oocytes retrieved

Cycle cancellation due to poor ovarian response

Number of cycles reaching the stage of embryo transfer

Number and quality of embryos

Number of cycles with frozen supernumerary embryos

Detailed description: Studies in primates showed that treatment with testosterone increased the number of growing follicles, lead to proliferation of granulosa and theca cells, while finally reduced the apoptosis of granulosa cells (Vendola et al., 1999; Weil et al., 1999). These studies further suggest that androgens may have a specific action in pre-antral and small antral follicles, prior to serving as substrate for estradiol synthesis in larger follicles and in this regard influence the responsiveness of the ovaries to gonadotropins and amplify the effects of FSH on the ovary. Despite the available evidence, only 3 small RCTs evaluated the effect of transdermal testosterone on infertile patients with poor ovarian response to stimulation. A pooled analysis of these studies demonstrated a benefit in clinical and ongoing pregnancy rates for testosterone pre-treated patients (González-Comadran et al., 2012). However, two of these trials were considerably small, whereas all of them restricted testosterone administration between 5 and 21 days prior ovarian stimulation. Evidence from basic research and early trials suggest that androgens should be administered for at least 2 months before initiation of ovarian stimulation (Casson PR, 2000), in order affect preantral follicles and equip them with more FSH receptors in an attempt to have a larger cohort of follicles surviving to the recruitable antral stage. Taking into account the promising results from recently conducted small RCTS, the investigators decided to perform a double blind placebo controlled randomized controlled trial, with adequate sample size, in order to test the effect of administration of transdermal testosterone in poor ovarian responders fulfilling the Bologna criteria, for 2 months prior ovarian stimulation in a long agonist protocol. The daily dose of transdermal testosterone gel (TTG) will be 0. 55gr (5. 5mg testosterone/day). The specific dose was selected based on previous pharmacokinetic studies in women according to which daily application of 5 mg of transdermal testosterone cream (Fooladi, 2014) or TTG (Singh et al. 2006, Nathorst-Böös et al., 2005) is likely to restore fT levels to the premenopausal reference range. Although no side effects had been described after pre-treatment with higher doses of 12. 5mg TTG for 21 days in a previous randomized controlled trial (Kim et al., 2011), it is likely that higher doses will result in supraphysiological TT and fT levels. Therefore the dose of 0. 55gr TTG (5. 5mg testosterone/day) has been selected for the T-TRANSPORT trial since this will restore TT and fT levels to levels above and within the upper normal reference range.

Minimum age: 18 Years. Maximum age: 43 Years. Gender(s): Female.

Criteria:

Inclusion Criteria: Eligible patients were considered women fulfilling the "Bologna criteria" for poor ovarian response. Two out of three of the following criteria were essential in order to classify a patient as poor ovarian responder:

- advanced maternal age (≥40 years) or any other risk factor for poor ovarian response

- a poor ovarian response (≤3 oocytes with a conventional stimulation protocol)

- an abnormal ovarian reserve test (AFC<7 follicles or AMH<1. 1 ng/ml).

Exclusion Criteria:

- Perimenopausal women with amenorrhea not having a regular cycle

- Uterine abnormalities

- Recent history of any current untreated endocrine abnormality;

- Unilateral or bilateral hydrosalpinx (visible on USS, unless clipped);

- Contraindications for the use of gonadotropins;

- Recent history of severe disease requiring regular treatment

- Use of androgens during the last 3 months

- Patients with shBG values <20nmol/L or >160nmol/L

- Azoospermia (sperm derived through Testicular sperm extraction (TESE))

Nikolaos P Polyzos, MD PhD, Phone: 003224749087, Email: n.polyzos@gmail.com

Universitair Ziekenhuis Brussel, Brussels 1090, Belgium; Recruiting
Nikolaos P Polyzos, Phone: +32476763203, Email: n.polyzos@gmail.com

The Fertility Clinic, Skive Regional Hospital, Skive, Denmark, Skive, Denmark; Not yet recruiting
Peter Humaidan

Hospital Universitario Quiron Dexeus, Barcelona, Spain; Not yet recruiting
Pedro N Barri, MD PhD

Quiron Madrid Hospital, Madrid, Spain; Not yet recruiting
Antonio Gosálvez Vega

Karolinska University, Stokholm, Sweden; Not yet recruiting
Jan Olofsson

University Hospital Basel, Basel, Switzerland; Not yet recruiting
Christian De Geyter, MD PhD

Related publications:

Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod. 2000 Oct;15(10):2129-32.

González-Comadran M, Durán M, Solà I, Fábregues F, Carreras R, Checa MA. Effects of transdermal testosterone in poor responders undergoing IVF: systematic review and meta-analysis. Reprod Biomed Online. 2012 Nov;25(5):450-9. doi: 10.1016/j.rbmo.2012.07.011. Epub 2012 Jul 26. Review.

Vendola K, Zhou J, Wang J, Famuyiwa OA, Bievre M, Bondy CA. Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Biol Reprod. 1999 Aug;61(2):353-7.

Weil S, Vendola K, Zhou J, Bondy CA. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab. 1999 Aug;84(8):2951-6.

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.

Singh AB, Lee ML, Sinha-Hikim I, Kushnir M, Meikle W, Rockwood A, Afework S, Bhasin S. Pharmacokinetics of a testosterone gel in healthy postmenopausal women. J Clin Endocrinol Metab. 2006 Jan;91(1):136-44. Epub 2005 Nov 1.

Nathorst-Böös J, Jarkander-Rolff M, Carlström K, Flöter A, von Schoultz B. Percutaneous administration of testosterone gel in postmenopausal women--a pharmacological study. Gynecol Endocrinol. 2005 May;20(5):243-8.

Fooladi E, Reuter SE, Bell RJ, Robinson PJ, Davis SR. Pharmacokinetics of a transdermal testosterone cream in healthy postmenopausal women. Menopause. 2015 Jan;22(1):44-9. doi: 10.1097/GME.0000000000000259.

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.

Starting date: April 2015
Last updated: April 16, 2015