The Effect of a Higher Dose of Dehydroepiandrosterone (DHEA) Supplementation in Poor Responders

Infertility Clinical Trial

— DHEA  

Official title:

The Effect of a Higher Dose of Dehydroepiandrosterone (DHEA) Supplementation on the Number of Oocytes Obtained During IVF in Poor Ovarian Responders

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02357472
• Other study ID #: JIAIE2014-03
• Status: Active, not recruiting
• Phase: Phase 4
• First received: January 17, 2015
• Last updated: November 16, 2015
• Start date: December 2014
• Est. completion date: December 2016

Study information

• Verified date: November 2015
• Source: ShangHai Ji Ai Genetics & IVF Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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) ( 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 50
• Est. completion date: December 2016
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 22 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Infertility

Intervention

Drug:
• dehydroepiandrosterone
high dose group treatment represent for 50mg t.i.d and standard dose group represents for normal treatment with 25mg t.i.d. Each patients in these two group will take one capsule each time and three times a day for three months before entering into IVF cycles.

Locations

Country	Name	City	State
China	Ji Ai Genetics and IVF center	Shang Hai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
ShangHai Ji Ai Genetics & IVF Institute

Country where clinical trial is conducted

China, 

References & Publications (10)

Barad D, Brill H, Gleicher N. Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function. J Assist Reprod Genet. 2007 Dec;24(12):629-34. Epub 2007 Dec 11. — View Citation

Barad D, Gleicher N. Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF. Hum Reprod. 2006 Nov;21(11):2845-9. Epub 2006 Sep 22. — View Citation

Barad DH, Gleicher N. Increased oocyte production after treatment with dehydroepiandrosterone. Fertil Steril. 2005 Sep;84(3):756. — View Citation

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. — View Citation

Casson PR, Santoro N, Elkind-Hirsch K, Carson SA, Hornsby PJ, Abraham G, Buster JE. Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein: a six-month trial. Fertil Steril. 1998 Jul;70(1):107-10. — View Citation

Gleicher N, Ryan E, Weghofer A, Blanco-Mejia S, Barad DH. Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve: a case control study. Reprod Biol Endocrinol. 2009 Oct 7;7:108. doi: 10.1186/1477-7827-7-108. — View Citation

Hartkamp A, Geenen R, Godaert GL, Bijl M, Bijlsma JW, Derksen RH. Effects of dehydroepiandrosterone on fatigue and well-being in women with quiescent systemic lupus erythematosus: a randomised controlled trial. Ann Rheum Dis. 2010 Jun;69(6):1144-7. doi: 10.1136/ard.2009.117036. Epub 2009 Oct 22. — View Citation

Jenkins JM, Davies DW, Devonport H, Anthony FW, Gadd SC, Watson RH, Masson GM. Comparison of 'poor' responders with 'good' responders using a standard buserelin/human menopausal gonadotrophin regime for in-vitro fertilization. Hum Reprod. 1991 Aug;6(7):918-21. — View Citation

Keay SD, Liversedge NH, Mathur RS, Jenkins JM. Assisted conception following poor ovarian response to gonadotrophin stimulation. Br J Obstet Gynaecol. 1997 May;104(5):521-7. Review. — View Citation

Ulug U, Ben-Shlomo I, Turan E, Erden HF, Akman MA, Bahceci M. Conception rates following assisted reproduction in poor responder patients: a retrospective study in 300 consecutive cycles. Reprod Biomed Online. 2003 Jun;6(4):439-43. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The number of mature oocytes obtained		up to 12 weeks
Other	Pregnancy rate	The rate of clinical pregnancy and ongoing pregnancy	2 weeks after transfer
Other	the numbers of fertilized embryos		up to 12 weeks
Other	the numbers of cleaved embryos		up to 12 weeks
Other	the numbers of transferred embryos		up to 12 weeks
Other	the numbers of top-quality embryos.	top-quality embryos are represented for >7cell on Day 3 and the fragments <20%	up to 12 weeks
Primary	The number of oocytes obtained	After 12 weeks treatment,the change of the number of oocytes obtained from the IVF cycle will be detected among the higher dose group ,normal dose group and placebo group	up to 12 weeks
Secondary	Antral follicle count (AFC)	9-10mm follicles	baseline and 12 weeks
Secondary	Follicle stimulating hormone (FSH) levels	The change of FSH levels in the three groups.	baseline and 12 weeks
Secondary	Estrogen 2 (E2)	Serum and follicular E2 levels	baseline and 12 weeks
Secondary	The number of follicles>10mm	The number of follicles>10mm represent for the ovarian reserve and response	up to 12 weeeks
Secondary	Antimüllerian hormone ( AMH ) level	The change of AMH levels in serum and follicular fluid	baseline and 12 weeks
Secondary	testosterone		baseline and 12 weeks
Secondary	Dehydroepiandrosterone-Sulfide (DHEA-S)		baseline and 12 weeks
Secondary	insulin-like growth factor-1 (IGF-1)		baseline and 12 weeks