Clinical trial NCT02357472: The Effect of a Higher Dose of Dehydroepiandrosterone (DHEA) Supplementation in Poor Responders
Official title: The Effect of a Higher Dose of Dehydroepiandrosterone (DHEA) Supplementation on the Number of Oocytes Obtained During IVF in Poor Ovarian Responders
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Infertility
Keywords: Reproductive aging
DHEA
poor ovarian responder
Lead sponsor: ShangHai Ji Ai Genetics & IVF Institute
Sponsor class: OTHER
First posted: 2015-02-06
Enrollment: 50
Sex: FEMALE
Minimum age (years): 22
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The supplementation of Dehydroepiandrosterone (DHEA) has been used in some centers for patients with previous poor ovarian reserve and response in an attempt to improve pregnancy outcomes. However, there still has controversy on the clinical effect on the 75mg/d for the use,especially in Asian people. Whether the double dosage of DHEA in patients with poor ovarian reserve and response in China can improve the IVF outcome with little side effect is unknown.

The aim of this randomized controlled study is to compare the effect of a higher dose (150mg daily) and a standard dose (75mg daily) of DHEA on the number of oocytes obtained in poor ovarian responders. The effect of DHEA action on the cumulus cells will be examined.

Detailed description: Consecutive infertile women attending the subfertility clinic at Shang Hai Ji Ai Genetics \&IVF Institute for IVF treatment will be approached. Those fulfilling the selection criteria stated below would be recruited and a written consent will be obtained after detailed explanation and counseling.

Poor ovarian responders are defined according to the Bologna criteria fulfilling 2 out of 3 of the following:

(i) Advanced maternal age (\>/= 40) or any other genetic or acquired risk factor for poor ovarian response(POR); (ii) Previous poor ovarian response (POR) (\</= 3 oocytes with a conventional stimulation protocol using at least 150 international units (IU) gonadotrophins per day) (iii) Abnormal ovarian reserve test \[i.e. antral follicle count (AFC) \< 5-7 or antimüllerian hormone (AMH) \< 0.5 - 1.1ng/ml\]

Alternatively, two episodes of POR after maximal stimulation are sufficient to define a patient as poor responder in the absence of advanced maternal age or abnormal ovarian reserve test(ORT).

Baseline assessment will be performed at early follicular phase (Day 2 or 3) at recruitment. Patient characteristics including age, Body Mass Index (BMI), and smoking status would be recorded and blood test including follicular stimulating hormone (FSH), estradiol (E2), testosterone, DHEA-S, full blood count, renal and liver function test would be checked. Pelvic scan will be performed to assess the total AFC and total ovarian volume.

Subjects will be randomized divided into two groups:

1. Standard dose group: Subjects will take DHEA (Lab Hercules™) 25mg three times a day for 12 weeks prior to the start of IVF treatment till the day of egg collection.
2. High dose group: Subjects will taking DHEA (Lab Hercules™) 50mg three times a day for 12 weeks prior to the start of IVF treatment till the day of egg collection.

Hormonal profile, ultrasound assessment, full blood count, renal and liver function test will be repeated in follicular phase (D2 or 3) of every month or cycle followed by a IVF treatment using antagonist protocol based on our standard departmental regimen. The human menopausal gonadotropin (hMG) injections were started at 300 international units (IU) for 2 days followed by 300 international units (IU) daily. Improvement of ovarian reserve markers would be assessed by the change in serum AMH between the time of recruitment and that after 6 and 12 weeks of DHEA. Cycle characteristics including the dose of gonadotrophins use, duration of stimulation, number of oocytes obtained, number of fertilized embryos and good quality embryos will be recorded and follicular fluid will be saved for hormonal profiles.

Statistics

1. Statistical tests

   Statistical comparisons will be performed according to the intention to treat principle by Student t test or Fisher's exact tests for normally distributed data and Mann-Whitney test for skewed data. Chi-square test would be used for binary variables. Statistical analyses will be performed using the Statistical Package for (the) Social Sciences (SPSS) software and a P-value of 0.05 would be considered statistically significant. Linear regression analysis / logistic regression analysis curve would be used to evaluate the age, BMI, smoking, FSH, E2, AMH, testosterone, DHEA-S, AFC, ovarian volume and duration of DHEA use for the prediction of improved ovarian reserve after DHEA supplementation.
2. Sample size estimation

The number of oocytes retrieved will be used as the primary outcome of the study. Based on our own database for patients undergoing IVF treatment, the mean oocytes obtained was 2.7 with a standard deviation (SD) of 1.4. Assuming an increase of oocytes obtained by 1.0 to be clinically significant, 18 subjects in each arm would be required to achieve a test of significance of 0.05 and a power of 0.8. Considering possible dropouts, we aim at recruiting 18 patients in each arm, i.e. 36 patients.

In order to compare one of the secondary outcome -- AMH (which has more relevance on the effect of ovarian response) with adequate power, based on our own database for patients undergoing IVF treatment, the mean AMH of the group with poor ovarian reserve is 0.8 with a SD of 0.6. Assuming an increase of number of oocyte retrieved by 0.5 to be clinically significant, 25 subjects in each arm would be required to achieve a test of significance of 0.01 and a power of 0.9. Totally 50 patients.

Eligibility criteria: Inclusion Criteria:

1. age\<45 years,
2. subfertility \>1 year, and
3. A previous POR (≤3 oocytes with a conventional stimulation protocol of at least 150 IU FSH per day); or
4. An abnormal ovarian reserve test (i.e. AFC ≤5-7 follicles or AMH ≤0.5-1.1 ng/ml).

Exclusion Criteria:

Patients were excluded if they:

1. had a history of ovarian cystectomy or oophorectomy,
2. had received cytotoxic chemotherapy,
3. had received pelvic irradiation, or
4. had a history of taking testosterone or DHEA supplementation

Primary outcomes:
measure: The number of oocytes obtained
timeFrame: up to 12 weeks
Secondary outcomes:
measure: Antral follicle count (AFC)
timeFrame: baseline and 12 weeks
measure: Follicle stimulating hormone (FSH) levels
timeFrame: baseline and 12 weeks
measure: Estrogen 2 (E2)
timeFrame: baseline and 12 weeks
measure: The number of follicles>10mm
timeFrame: up to 12 weeeks
measure: Antimüllerian hormone ( AMH ) level
timeFrame: baseline and 12 weeks
measure: testosterone
timeFrame: baseline and 12 weeks
measure: Dehydroepiandrosterone-Sulfide (DHEA-S)
timeFrame: baseline and 12 weeks
measure: insulin-like growth factor-1 (IGF-1)
timeFrame: baseline and 12 weeks
Other outcomes:
measure: The number of mature oocytes obtained
timeFrame: up to 12 weeks
measure: Pregnancy rate
timeFrame: 2 weeks after transfer
measure: the numbers of fertilized embryos
timeFrame: up to 12 weeks
measure: the numbers of cleaved embryos
timeFrame: up to 12 weeks
measure: the numbers of transferred embryos
timeFrame: up to 12 weeks
measure: the numbers of top-quality embryos.
timeFrame: up to 12 weeks
Locations:
city: Shang Hai
country: China
facility: Ji Ai Genetics and IVF center
state: Shanghai
Study officials:
affiliation: Shang Hai JIAi genetics & IVF center
name: Xiao Xi Sun, PHD,MD
role: STUDY_CHAIR
affiliation: Shang Hai JIAi genetics & IVF center
name: Jing Fu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Shang Hai JIAi Genetics & IVF center
name: Ying Su Liu, PHD,MD
role: STUDY_DIRECTOR
References:
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