Comparison Between Testosterone and Estradiol Over the Homogenization of Follicular Cohort

Sponsor

Hospital de Clinicas de Porto Alegre (Other)

Overall Status

Unknown status

CT.gov ID

NCT03238092

Collaborator

(none)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

In vitro fertilization(IVF) with Gonadotropin-releasing hormone (GnRH) antagonist is one of the most used protocol for the treatment of infertile couples nowadays. Despite several advantages over GnRH agonist, the antagonist may be associated with a slightly reduction in pregnancy rates.

Several medications have been tested in order to increase ovarian response to ovulation induction, including estradiol and testosterone. A clinical trial in women with IVF indication will be performed and this women will be randomly assigned to receive topic testosterone, oral estradiol or no pre-treatment prior to IVF with human Chorionic Gonadotropin (hMG) and GnRH antagonist. The primary endpoint will be the size and number of follicles on the beginning of the cycle, after pre-treatment.

Condition or Disease	Intervention/Treatment	Phase
Fertility Disorders	Drug: Testosterone Drug: Estradiol	Phase 3

Detailed Description

One of the key-words to a successful IVF it is the response to the ovarian controlled stimulation. Nowadays, one of the most common protocols includes exogenous gonadotropins and GnRH antagonist, followed by IVF. The GnRH antagonist avoids the premature peak of LH and has advantages in relation to the GnRH agonist; however it might have a negative effect over the pregnancy rate. One possible explanation is the heterogeneity of the follicular cohort at the moment of ovarian puncture, due to the rise of FSH at luteal-follicular transition. The estrogen can inhibits this rise of Follicle-Stimulating Hormone (FSH), resulting in a more synchronic cohort. Previous studies have demonstrated a reduction in the cancellation rates with estradiol in the luteal phase of the cycle prior to the beginning of IVF using GnRH antagonist protocol, with a trend towards better quality of transferred embryos and better implantation rates when compared to the standard protocol with antagonist. The use of androgens is based on the assumption that they generate an increase in FSH receptors in the granulosa cells, increase in follicular growth and estrogen production, according to animal and human studies. Despite promising initial results, further studies are needed to evaluate the benefit of testosterone as a pretreatment in women undergoing IVF.

The study protocol is the following: Around the 20th day of the cycle prior to the choice of IVF, transvaginal pelvic ultrasound and serum progesterone dosage will be performed in all patients. After confirmation of ovulation and no contraindications for the continuation of the study, according to the randomization, testosterone gel, estradiol oral or no treatment will be initiated. Both medications will be continued until the first day of subsequent menstruation. After the menses, between the second and third day of the cycle, a new transvaginal ultrasound will be performed and blood tests will be collected for the dosage of FSH, Luteinizing Hormone (LH), progesterone and estradiol. On the same day, subcutaneous hMG (Menopur®) will be started at a dose between 150 and 300 IU / day, according to age and HAM, which will be subsequently adjusted according to the ovarian response on serial ultrasonography. When the largest follicle reaches a mean diameter of 14 mm, the GnRH antagonist (Orgalutran ®) will be initiated to prevent early LH peak, and monitored follicular growth with echography every 1-2 days. HCG will be administered at a dose of 10,000 IU (Choriomon®) when three or more follicles reach a mean diameter of 17 mm. After 36h, follicular puncture will be performed transvaginally, under general anesthesia. Embryo transfer will occur between the third and fifth day after in vitro fertilization. Luteal support will be given with administration of progesterone 600 mg / day vaginally, initiated after the transfer and maintained until the first trimester of pregnancy if it occurs. Serum beta-HCG measurement will be performed on the 12th day after transfer, for evaluation of pregnancy implantation. Clinical gestation will be considered when there is evidence of intrauterine embryo with cardiac beats present on the ultrasound, after 6 weeks of transfer of the embryo (s).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

26 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

As a pre-treatment for in vitro fertilization, one arm will receive transdermic testosterone , one arm will receive oral estradiol and a third arm will be the control group, without pre-treatmentAs a pre-treatment for in vitro fertilization, one arm will receive transdermic testosterone , one arm will receive oral estradiol and a third arm will be the control group, without pre-treatment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Comparison Between Testosterone and Estradiol Over the Homogenization of Follicular Cohort: a Randomized Clinical Trial

Anticipated Study Start Date :

Aug 1, 2017

Anticipated Primary Completion Date :

Jan 1, 2018

Anticipated Study Completion Date :

Mar 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Estradiol group In the late luteal phase, the participant will receive estradiol 2mg and will take orally a total of 4mg per day (2mg in the morning and 2 mg in the night) until the next menstrual bleeding. After that, the patient will descontinue the medication and proceed to the regular in vitro fertilization protocol.	Drug: Estradiol oral estradiol during the late luteal phase. Other Names: estradiol valerato
No Intervention: Control group No pre-treatment will be administrated. The regular in vitro fertilization protocol will be performed.
Experimental: Testosterone group Testosterone 25mg (10mg/g) transdermal during the late luteal phase, until the next menstrual bleeding.	Drug: Testosterone testosterone gel daily during the late luteal phase. Other Names: androgel

Arm

Intervention/Treatment

Active Comparator: Estradiol group

In the late luteal phase, the participant will receive estradiol 2mg and will take orally a total of 4mg per day (2mg in the morning and 2 mg in the night) until the next menstrual bleeding. After that, the patient will descontinue the medication and proceed to the regular in vitro fertilization protocol.

Drug: Estradiol

oral estradiol during the late luteal phase.

Other Names:

estradiol valerato

No Intervention: Control group

No pre-treatment will be administrated. The regular in vitro fertilization protocol will be performed.

Experimental: Testosterone group

Testosterone 25mg (10mg/g) transdermal during the late luteal phase, until the next menstrual bleeding.

Drug: Testosterone

testosterone gel daily during the late luteal phase.

Other Names:

androgel

Outcome Measures

Primary Outcome Measures

number of antral follicles [15 days after intervention]
Number of follicles measured by transvaginal ultrasound during the first or second day after menstruation

Secondary Outcome Measures

follicular cohort homogeneity [15 days after intervention]
The comparison of medium follicular diameter (also measured by transvaginal ultrasound) of all the follicles during the first or second day after menstruation
metaphase II oocytes [30 days]
the number of metaphase II oocytes
gonadotrophin use [30 days]
number of units of gonadotrophin used during the in vitro fertilization protocol
number of embryos [30 days]
the number of embryos assessed during the in vitro fertilization
pregnancy [6 weeks]
clinical pregnancy, defined by the evidence of intrauterine embryo in the ultrasound

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 39 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Regular cycles (between 25-34 days)
In vitro fertilization indication for male cause, unexplained infertility or tubal factor
Both ovaries
Thyroid-stimulating hormone(TSH) < 2,5 mU/L
Anti-Müllerian hormone (AMH) between 1-5 ng/ml
Body Mass Index (BMI) < 30