The LUTEAL Trial: Luteal Stimulation vs. Estrogen Priming Protocol
The LUTEAL Trial: Luteal Stimulation vs. Estrogen Priming Protocol
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 < 5 mIU/mL, the patient will begin 450 IU of daily
 injectable gonadotropins: 150 IU of hMG (Menopur®, Ferring Pharmaceuticals) and 300 IU of
 recombinant FSH (rFSH) (Gonal F®,Serono; or Follitropin beta (Follistim®, Organo)). The
 specific rFSH chosen will be based on the individual patient's insurance coverage. The
 patient will perform daily injections during the course of her stimulation, and will also
 take oral Clomiphene citrate 100mg daily for the first five days of the stimulation. FSH dose
 will be titrated during the stimulation (per physician discretion) based on serum estradiol
 levels and ovarian response to a minimum of no gonadotropins and a maximum of 600 IU daily.
 She will present for follicular monitoring ultrasound and serum blood tests on stimulation
 day 3-4, 5-6, and 7-8-~15. Gonadotropin releasing hormone (GnRH) antagonist (Ganirelix,
 Organon; and cetrorelix, Serono) will be started daily once either (1) serum estradiol level
 reaches > 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 < 1.0 ng/mL, and bHCG < 5 mIU/mL, on cycle day 2-3 the patient will stop her
 estrogen patches and start 450 IU of daily injectable gonadotropins: 150 IU of hMG (Menopur®,
 Ferring Pharmaceuticals) and 300 IU of recombinant FSH (rFSH) (Gonal F®,Serono; or
 Follitropin beta (Follistim®, Organo)). The specific rFSH chosen will be based on the
 individual patient's insurance coverage. Estrogen patch will be removed the day of starting
 gonadotropin injections. The patient will perform daily injections during the course of her
 stimulation, and will also take oral Clomiphene citrate 100mg daily for the first five days
 of the stimulation. FSH dose will be titrated during the stimulation (per physician
 discretion) based on serum estradiol levels and ovarian response to a minimum of no
 gonadotropins and a maximum of 600 IU daily. She will present for follicular monitoring
 ultrasound and serum blood tests on stimulation day 3-4, 5-6, and 7-8-~15. Gonadotropin
 releasing hormone (GnRH) antagonist (Ganirelix, Organon; and cetrorelix, Serono) will be
 started daily once either (1) serum estradiol level reaches > 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.
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