FSH and LH Versus FSH Alone for Ovarian Stimulation in Non-hormone Sensitive Onco-fertility Patients

The proposed study is a superiority, randomized controlled trial examining the effect of FSH and rLH (Luveris) versus FSH alone on the number of mature oocytes available for cryopreservation in non-hormone sensitive onco-fertility patients. These patients include those diagnosed with malignancy other than breast, uterine and ovarian cancer.

Given that the care of oncology patients is time sensitive, a random start of the treatment cycle is the usual approach in Mount Sinai Fertility clinic, with no prior priming. The patient has a random serum levels of estrogen, progesterone, LH, FSH and HCG levels. A transvaginal ultrasound is performed as well, and the stage of the cycle is determined. Based on the stage of the cycle, gonadotropin starting time is planned accordingly.

• Early follicular phase: Gonadotropin stimulation started. A GnRH antagonist will be given once the dominant follicle measures >1.4 cm.
• Mid to late follicular phase: patients who have a dominant follicle >1.5 cm with an E2 >300 and a progesterone <5 will be triggered usually with HCG (Ovidrel 250 mcg subcutaneous). After three days gonadotropin stimulation is started.
• Start of luteal phase: start gonadotropin stimulation and once the dominant follicle measure >1.4, a GnRH antagonist will be given.

Patients will be randomly assigned in a 1:1 ratio to either treatment or control group. Treatments in each of the trial arms will be as follows:

• Treatment arm: Patients will self-administer a subcutaneous injection of Gonal-F (FSH) in addition to Luveris daily until a pre-set criteria to trigger ovulation is reached.
• Control arm: Patients will self-administer a subcutaneous injection of Gonal-F (FSH) daily until a pre-set criteria to trigger ovulation is reached.

Transvaginal ultrasound and bloodwork monitoring is initiated to monitor the ovarian response.

Once the patient meets one of the following two criteria

• A serum estradiol (E2) of greater than 2,000 pmol/L
• A follicle measuring greater than 14 mm,

A daily, subcutaneous injection of a GnRH antagonist (Cetrotide or Ganirelix 0.25 mg) will be administered by the patient subcutaneously to prevent an endogenous surge in LH. Monitoring of the ovarian response will continue until there are 3 or more follicles visualized by transvaginal ultrasound with a mean diameter of ≥17 mm. Ovulation will be subsequently triggered with a subcutaneous injection of HCG or GnRH agonist depending on the managing IVF physician. Twelve hours after their trigger medication, patients will return to the clinic for standard blood work including LH and progesterone. This is a standard confirmatory blood test to confirm that an endogenous LH surge has occurred. In approximately less than 5% of cases, the GnRH-a trigger fails to elicit an optimal surge, which may require a "rescue" low-dose hCG trigger to be administered 24 hours following the initial trigger. The decision to administer a "rescue" trigger will be at the discretion of the managing IVF physician. Transvaginal, ultrasound-guided oocyte retrieval will be performed approximately 36 hours following the administration of the initial trigger.

Once the oocytes are retrieved, the availability of sperm will determine whether the partner's sperm or donor sperm will be used. If the patient desires to cryopreserve oocytes, mature oocytes will be cryopreserved by vitrification process. If embryo cryopreservation is planned, the retrieved oocytes will be fertilized in the lab using traditional IVF or ICSI. Embryos will be grown to day 5 and all "good quality" blastocysts will be cryopreserved using vitrification. At Mount Sinai Fertility clinic, day 5/6 embryos are considered "good quality" for cryopreservation if they are at least a grade 2BB (or above) on day 5 and/or a 3CC (or above) on day 6, according to the classification system by Gardner and Schoolcraft, 1999. Patients will undergo a freeze-all cycle, with no fresh transfer of embryos.

The primary outcome measure will be the total number of mature (MII) oocytes available for cryopreservation.

Secondary outcome measures will include the following:

• Total number of oocytes retrieved per cycle
• Ratio of mature (MII) to immature oocytes
• Total number of mature oocytes (MII) retrieved per IVF/ICSI cycle
• Ratio of mature (MII) to immature oocytes per IVF/ICSI cycle
• Number of two pronuclei (2PN) zygotes
• Fertilization rate, which will include two outcomes each defined as follows:

Definition 1: number of 2PN zygotes divided by the number of mature oocyte(s) fertilized per IVF/ICSI cycle.

Definition 2: number of 2PN zygotes divided by the number of oocytes incubated with at least 10,000 sperm per IVF cycle.

• Total number of day 3 embryos
• Total number of good quality day 5 embryos available for cryopreservation determined by a blinded embryologist using the classification system by Gardner and Schoolcraft, 1999.
• Incidence of moderate to critical OHSS based on the classification criteria by Mathur et al. 2005

Inclusion criteria

• Between the ages of 18 and 40.
• Undergoing IVF for fertility preservation (freezing all oocytes or embryos)
• Diagnosed with a non-hormone sensitive malignancy (malignancy other than breast, uterine and ovarian cancer)
• GnRH antagonist protocol (standard of care for all fertility preservation patients)

Exclusion criteria

• Any contraindication to treatment with gonadotropins (including medical history or risk factors for TE, hypersensitivity to gonadotropins or to any of the excipients).
• Congenital hypogonadotropic hypogonadism unrelated to the oncological condition.
• Previous adverse or allergic reaction to luteinizing hormone or any of its drug components.
• Had prior radiotherapy to the abdomen or pelvis
• Prior chemotherapy
• Prior history of deep vein thrombosis, or pulmonary embolism
• Patients with a diagnosis of hormone sensitive cancer including ovarian, uterine, or mammary carcinoma
• Patients with uncontrolled thyroid or adrenal failure
• Patients with active, untreated tumors of the hypothalamus and pituitary gland
• Patients who are lactating
• Patients with a known diagnosis of primary ovarian failure
• Previous participant of this study