Dehydroepiandrosterone Versus Growth Hormone in Women Undergoing ICSI With Expected Poor Ovarian Response

300 women with expected poor ovarian response (POR) undergoing in vitro fertilization or intra-cytoplasmic sperm injection (ICSI) will be randomly divided into 2 equal groups using computer generated random numbers. Group 1 will receive Dehydroepiandrosterone (DHEA) 25 mg ( DHEA 25mg, Natrol , USA) t.d.s daily for 12 weeks before starting IVF/ICSI cycle and a placebo similar to growth hormone (GH) daily from day 6 of stimulation until the day of human chorionic gonadotrophin (hCG) trigger. Group 2 will receive an oral placebo t.d.s. daily for 12 weeks before ICSI in addition to GH (Somatotropin, Sedico, Egypt) 4 IU on day 6 of hMG stimulation in a daily dose of 2.5 mg subcutaneous (SC) until the day of hCG triggering.

Patients included in the study will be subjected to full history taking and clinical examination. On the second day of menstruation serum FSH, LH, Prolactin and Oestradiol will be assessed and the antral follicular count (AFC) will be assessed using a vaginal ultrasound scan. AFC will be defined as the number of follicles measuring 3-10mm.

All patients will have gonadotropin antagonist protocol with Human menopausal gonadotrophin (hMG) stimulation until the day of hCG administration. On the day of hCG administration, ovarian ultrasound scan will be performed using a transvaginal probe. Oocytes will be aspirated 34-36 hours after HCG administration. Oocytes will be fertilized and embryos will be transferred. Both groups will be compared regarding the proportion of ongoing pregnancy.

Study Overview

• Status: Unknown
• Conditions: Subfertility
• Intervention / Treatment: Drug: DHEA; Drug: Placebo 2; Drug: Growth Hormone-Releasing Hormone; Drug: Placebo 1

Detailed Description

The study will be conducted in Cairo university hospitals and Dar Al-Teb Infertility and Assisted conception center, Giza Egypt. All patients attending the centre will be evaluated for expected ovarian response. Patients fulfilling the Bologna criteria definition of poor ovarian response will be invited to participate in the study and to sign informed consent forms.

300 women with expected poor ovarian response undergoing IVF/ICSI will be randomly divided into 2 equal groups using computer generated random numbers. Group 1 will receive DHEA 25 mg ( DHEA 25mg, Natrol , USA) t.d.s daily for 12 weeks before starting IVF/ICSI cycle and a placebo similar to GH daily from day 6 of stimulation until the day of hCG trigger. Group 2 will receive an oral placebo t.d.s. daily for 12 weeks before ICSI in addition to GH Growth hormone (Somatotropin, Sedico, Egypt) 4 IU on day 6 of hMG stimulation in a daily dose of 2.5 mg SC until the day of hCG triggering.

Patients included in the study will be subjected to full history taking and clinical examination. On the second day of menstruation serum FSH, LH, Prolactin and Oestradiol will be assessed and the antral follicular count (AFC) will be assessed using a vaginal ultrasound scan. AFC will be defined as the number of follicles measuring 3-10mm.

All patients will have gonadotropin antagonist protocol with Human menopausal gonadotrophin (HMG) stimulation until the day of (Human chorionic gonadotrophin (HCG) administration. On the second day of menstruation serum FSH, LH, Prolactin and Oestradiol will be assessed and the antral follicular count (AFC) will be assessed using a vaginal ultrasound scan. AFC will be defined as the number of follicles measuring 3-10mm.

The stimulation protocol will start on day 2 using 450-300 IU HMG ( Merional® IBSA, Lugano, Switzerland) and gonadotrophin releasing hormone antagonist, cetrorelix (Cetrotide® Merck Serono, Darmstadt, Germany) 0.025 mg daily. Gonadotropins will be administered for 4 to 5 days, after which the dose will be adjusted according to the ovarian response. The ovarian response will be monitored by transvaginal ultrasound and serum E2 levels. When three or more follicles reached a maximum diameter of 16 mm, highly purified HCG 5000 or 10,000 IU (Choriomon ®IBSA) will be administered. The procedure will be cancelled if less than 3 follicles 16 mm in size are present 12 days after starting gonadotropins despite doses reaching 450 IU. The cycle will be also cancelled if there is risk of ovarian hyperstimulation like massive ovarian enlargement or serum estradiol exceeds 3000pg/L Transvaginal oocyte retrieval will be performed 34-36 h after the administration of HCG. Oocytes will be fertilized either via IVF or ICSI based on the couple's history. Fertilization will be assessed 16-18 h after IVF or ICSI . Embryos will be transferred on Day 3 or 5. Vaginal tablets containing progesterone (Prontogest® IBSA) 400 mg/day will be given when fertilization is confirmed. A pregnancy test will be done 2 weeks after embryo transfer. For patients with a positive pregnancy test, progesterone is to be continued for an additional 4 weeks. Clinical pregnancy will be defined as Visualization of an intrauterine gestational sac 5 weeks after embryo transfer. And ongoing pregnancy will be defined as the sonographic confirmation of fetal heart pulsations at 12 weeks.

Sample size calculation:

Investigators are planning a study of independent cases and controls with 1 control(s) per case. Kotb et al found that the ongoing pregnancy rate in women undergoing IVF/ICSI with expected POR according to the Bologna controls is 0.285. On the other hand Bassiouny et al found that the ongoing pregnancy rate in women undergoing ICSI with expected POR who received growth hormone is 0.147, investigators will need to study 138 case patients who will receive DHEA and 138 patients who will receive GH to be able to reject the null hypothesis that the ongoing pregnancy rates for DHEA and GH are equal with probability (power) 0.8. Investigators will add 12 patients to each arm to account for missing data and dropout patients. The Type I error probability associated with this test of this null hypothesis is 0.05. Investigators will use an uncorrected chi-squared statistic to evaluate this null hypothesis.

The primary outcome will be the ongoing pregnancy rate defined as sonographic confirmation of fetal heart beat at 12 weeks of gestation.

• Study Type: Interventional
• Enrollment (Anticipated): 210
• Phase: Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • Recruiting
    • Cairo University Hospitals
  • Cairo, Egypt
    • Recruiting
    • Dar AlTeb subfertility centre
    • Sub-Investigator: Mohamed MM Kotb, MD
    • Sub-Investigator: Ahmed MA AwadAllah, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• women undergoing IVF/ICSI with POR according to the Bologna criteria

Exclusion Criteria:

• Body mass index >35 Kg/m2.
• women with a single ovary.
• Allergy to DHEA.
• Diabetic women on insulin as insulin lowers DHEA levels and might reduce its effectiveness

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: DHEA; Women will receive oral DHEA 25 mg t.d.s. 12 weeks before ICSI	Drug: DHEA; Women will receive oral DHEA 25 mg t.d.s. 12 weeks before ICSI.; Drug: Placebo 2; Women will receive a placebo injection similar to growth hormone daily from day 6 of hMG stimulation until the day of hCG triggering.
Active Comparator: Growth hormone; Women will receive 4 IU of growth hormone on day 6 of hMG stimulation in a daily dose of 2.5 mg SC until the day of hCG triggering	Drug: Growth Hormone-Releasing Hormone; Women will receive 4 IU of growth hormone on day 6 of hMG stimulation in a daily dose of 2.5 mg SC until the day of hCG triggering; Drug: Placebo 1; Women will receive an oral placebo similar to DHEA for 12 weeks before ICSI.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ongoing pregnancy	ongoing pregnancy will be confirmed by the presence of fetal cardiac pulsations by a transvaginal ultrasound 12 weeks after embryo transfer.	12 weeks after embryo transfer

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical pregnancy	clinical pregnancy will be confirmed by the presence of an intrauterine gestational sac using a transvaginal ultrasound 5 weeks after embryo transfer.	5 weeks after embryo transfer

Collaborators and Investigators

• Sponsor: Cairo University
• Investigators: Principal Investigator: AbdelGany M Hassan, Cairo University

Publications and helpful links

General Publications

• Kotb MM, Hassan AM, AwadAllah AM. Does dehydroepiandrosterone improve pregnancy rate in women undergoing IVF/ICSI with expected poor ovarian response according to the Bologna criteria? A randomized controlled trial. Eur J Obstet Gynecol Reprod Biol. 2016 May;200:11-5. doi: 10.1016/j.ejogrb.2016.02.009. Epub 2016 Feb 21.
• Bassiouny YA, Dakhly DMR, Bayoumi YA, Hashish NM. Does the addition of growth hormone to the in vitro fertilization/intracytoplasmic sperm injection antagonist protocol improve outcomes in poor responders? A randomized, controlled trial. Fertil Steril. 2016 Mar;105(3):697-702. doi: 10.1016/j.fertnstert.2015.11.026. Epub 2015 Dec 13.
• Dakhly DM, Bayoumi YA, Gad Allah SH. Which is the best IVF/ICSI protocol to be used in poor responders receiving growth hormone as an adjuvant treatment? A prospective randomized trial. Gynecol Endocrinol. 2016;32(2):116-9. doi: 10.3109/09513590.2015.1092136. Epub 2015 Sep 29.
• Bayoumi YA, Dakhly DM, Bassiouny YA, Hashish NM. Addition of growth hormone to the microflare stimulation protocol among women with poor ovarian response. Int J Gynaecol Obstet. 2015 Dec;131(3):305-8. doi: 10.1016/j.ijgo.2015.05.034. Epub 2015 Aug 23.

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Anticipated): April 1, 2017
• Study Completion: December 7, 2022

Study Registration Dates

• First Submitted: April 8, 2016
• First Submitted That Met QC Criteria: April 12, 2016
• First Posted (Estimate): April 13, 2016

Study Record Updates

• Last Update Posted (Estimate): July 6, 2016
• Last Update Submitted That Met QC Criteria: July 3, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infertility; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormones; Growth Hormone-Releasing Hormone
• Other Study ID Numbers: sub 13

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No