the luteal trial: luteal stimulation vs. estrogen priming protocol

Conditions: Infertility; Diminished Ovarian Reserve; IVF

Summary: ovarian reserve defines the quantity and quality of the ovarian primordial follicular pool. diminished ovarian reserve (dor) indicates a reduction in the quantity of ovarian follicular pool to less than expected for age. it is an important cause of infertility in many couples. to date, there is no clear consensus in the literature on the definition of diminished ovarian reserve, and it is unclear whether low oocyte yield results from an abnormal atresia rate of the follicle pool, or from a lower follicle pool at birth or whether it can just occur as a normal variation in the population. the ovarian response to controlled ovarian stimulation with gonadotropins (for example, for in vitro fertilization) is largely determined by the ovarian reserve, and there are numerous different ovarian stimulation protocols that are employed to try and increase the oocyte yield of a particular cycle. there is no consensus on which, if any, of these protocols are superior and preferred for patient with dor. luteal gonadotropin stimulation is a protocol of controlled ovarian stimulation (cos) for use in assisted reproductive technologies (art) that has emerged over the past decade as an acceptable alternative to the classic follicular gonadotropin stimulation. the luteal estradiol patch protocol was introduced in 2005 in patients with poor response to controlled ovarian stimulation (cos) and to address the phenomenon of early follicle recruitment in patients with diminished ovarian reserve (dor). luteal gonadotropin stimulation can potentially achieve the same effect by initiating follicular recruitment for ivf prior to the body's own premature recruitment. our hypothesis is that the luteal stimulation protocol and estradiol priming protocol are equivalent with regard to the outcome of number of mature oocytes retrieved. patients who will be undergoing controlled ovarian stimulation and who have a diagnosis of diminished ovarian reserve will be considered for this trial, and enrolled if meeting all inclusion and no exclusion criteria.

patients who will be undergoing controlled ovarian stimulation and who have a diagnosis of diminished ovarian reserve will be considered for this trial, and enrolled if meeting all inclusion and no exclusion criteria. patients will be randomized to one of two possible stimulation cycles as will be described. luteal phase ovarian stimulation (lpos) patients will present for an appointment on approximately day 15-18 of her menstrual cycle. if serum progesterone \>3 ng/ml, and bhcg \ 400 pg/ml, lead follicle size \> 13mm, or (2) on stimulation day 6. once patient are ready for ovulation trigger as determine by physician, 5-10,000 units of human chorionic gonadotropin (novarel®: ferring pharmaceuticals; or pregnyl®: schering-plough) will be administered. a patient's trigger shot could be changed to include a gnrh agonist (i.e luprolide acetate 40 iu) if deemed clinically necessary for ovarian hyperstimulation syndrome prevention. on the morning after hcg administration, patients' blood will be drawn and serum analyzed for hcg concentration to ensure adequate absorption (mean time 8-10 hours). transvaginal oocyte retrieval will be performed 35 to 37 hours after hcg trigger. all metaphase ii oocytes will be fertilized with intracytoplasmic sperm injection (icsi) or ivf per patient request and laboratory protocol. embryos will be cultured to the blastocyst stage and vitrified on day 5-7. if patient requests preimplantation genetic testing for aneuploidy (pgt-a), an embryo biopsy will be performed on day 5-7 of development prior to vitrification, and biopsy specimen will be sent to an outside laboratory for chromosome analysis. luteal estradiol priming protocol (e2 prime) patients will present for an appointment on approximately day 18-21 of her menstrual cycle. if serum progesterone \>3 ng/ml, and bhcg \< 5 miu/ml, the patient will begin estradiol patches (vivelle dot 0.1mg, novartis pharmaceuticals; or climara, bayer) and change them every other day. she will also take daily gonadotropin releasing hormone (gnrh) antagonist (ganirelix, organon; and cetrorelix, serono) for the following three days. patients will then present for a baseline appointment with onset of her menses. if serum progesterone \ 400 pg/ml, lead follicle size \> 13mm, or (2) on stimulation day 6. once patient are ready for ovulation trigger as determine by physician, 5-10,000 units of human chorionic gonadotropin (novarel®: ferring pharmaceuticals; or pregnyl®: schering-plough) will be administered. a patient's trigger shot could be changed to include a gnrh agonist (i.e luprolide acetate 40 iu) if deemed clinically necessary for ovarian hyperstimulation syndrome prevention. on the morning after hcg administration, patients' blood will be drawn and serum analyzed for hcg concentration to ensure adequate absorption (mean time 8-10 hours). transvaginal oocyte retrieval will be performed 35 to 37 hours after hcg trigger. all metaphase ii oocytes will be fertilized with intracytoplasmic sperm injection (icsi) or ivf per patient request and laboratory protocol. embryos will be cultured to the blastocyst stage and vitrified on day 5-7. if patient requests preimplantation genetic testing for aneuploidy (pgt-a), an embryo biopsy will be performed on day 5-7 of development prior to vitrification, and biopsy specimen will be sent to an outside laboratory for chromosomal analysis. outcomes between the two stimulation protocols will be compared.

Eligibility criteria:
inclusion criteria: 1. provision of signed and dated informed consent form 2. stated willingness to comply with all study procedures and availability for the duration of the study 3. female aged 20 - 45 4. regular menstrual cycles between 21 and 40 days 5. presence of both ovaries 6. meets criteria for dor by the recent asrm/acog committee opinion 1. antimüllerian hormone (amh) value less than 1 ng/ml 2. antral follicle count less than 5-7 and 3. follicle-stimulating hormone (fsh) greater than 10 iu/l or 4. a history of poor response to in vitro fertilization stimulation (fewer than four oocytes at time of egg retrieval). exclusion criteria: 1. oocyte donation cycle 2. oocyte freezing cycle 3. current ovarian cyst \> 3cm 4. anovulatory or oligo-ovulatory (\<6 ovulation per year) 5. previous oophorectomy 6. exposure to cytotoxic or pelvic irradiation 7. planned aromatase inhibitor usage during current ovarian stimulation 8. sensitizing or ovarian stimulating therapy in the past one month additional contraindications to this study re, as follows (because such patients cannot receive an estrogen patch): 9. undiagnosed abnormal genital bleeding 10. known, suspected, or history of breast cancer 11. known or suspected estrogen-dependent neoplasia 12. active dvt, pe, or a history of these conditions 13. active arterial thromboembolic disease (for example, stroke and mi), or a history of these conditions 14. known anaphylactic reaction or angioedema with estradiol patches 15. known liver impairment or disease 16. known protein c, protein s, or antithrombin deficiency, or other known thrombophilic disorders

Keywords: ivf in vitro fertilization dor diminished ovarian reserve controlled ovarian stimulation