GnRH AgonistFSHLong Downregulation Protocol

This protocol (Fig. 2) is currently the protocol of choice for first cycle patients and previously normal or high responders in many IVF programs. A GnRH agonist [Leuprolide, 1 mg SC, Buserelin 600 mg SC; or Nafarelin acetate (Synarel)], 400 mg nasal spray, is given for 10-14 days before starting gonadotropin treatment ("long-protocol"), and may be commenced in the mid-luteal phase of the previous cycle or on day 2 of the cycle. We, in addition to other researcher found that pituitary suppression was more effective when the therapy commenced in the mid-luteal phase of the previous cycle

Down Regulation

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Blood tests

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Day of the cyclfl 21 £2233425 26 573829 3035 42 1 3 3 4 5 6 7 S B 10 11 13 13 14 15 16 17 16 19 30 3t33 333a 253627 33 3&30

'5000 fu given praferaHy on day 11 depending on Ultrasound and blood test results "'34 hours after HCG injection

Day of the cyclfl 21 £2233425 26 573829 3035 42 1 3 3 4 5 6 7 S B 10 11 13 13 14 15 16 17 16 19 30 3t33 333a 253627 33 3&30

'5000 fu given praferaHy on day 11 depending on Ultrasound and blood test results "'34 hours after HCG injection

Figure 2 A representation of the luteal-phase commencement long downregulation protocol using FSH for ovarian stimulation for assisted reproductive technology. Abbreviations: hCG, human chorionic gonadotropin; GnRH, gonadotrophin-releasing hormone; FSH, follicle-stimulating hormone.

rather than in the early follicular phase of the treatment (35). Urbancsek and Witthaus (41) found that clinical pregnancy and live birth rates were better when a GnRH agonist was started in the mid-luteal phase rather than in the early follicular phase. Another advantage in commencing the analog in the mid-luteal phase was the decreased occurrence of ovarian cysts compared with commencing the GnRH agonist at the beginning of the follicular phase (42). These cysts, especially if functional, should be aspirated before commencing gonadotropin treatment.

Suggested criteria for pituitary-ovarian downregulation are E2 levels <180 pmol/L, LH levels <2 IU/L, and P4 levels <2 nmol/L. FSH commences after achievement of adequate downregulation and continues by daily injections according to individual endocrine and ovarian ultrasonic response until the day before the human chorionic gonadotropin (hCG) injection. A 5000 IUIM injection is given when the follicular cohort consists of at least three follicles of 17-20 mm in diameter and serum E2 level is appropriately rising. Egg pick-up follows 36 hr later.

Disadvantages of this protocol include a greater consumption of GnRH agonist and FSH and, therefore, greater patient cost, as well as the uncertainty of possible pregnancy upon initiation of GnRH agonist treatment if the GnRH analog is started on day 21 of the previous cycle.

Table 1 Follicle-Stimulating Hormone Starting Dose in In Vitro Fertilization Ovarian Stimulation Protocols

Patient group

Dose (IU/day)

First cycle <37 year old

150

First cycle with baseline scan suggesting PCOS

112

First cycle patient 37-39 year old

225

First cycle patient >40 year old

300

Previous normal response (>5 oocytes)

150

Previous OHSS

75

Previous poor response (serum E2, 5th percentile)

450

BMI >30 kg/m2 (PCOS excluded)

Increase by 75

Severe endometriosis

Increase by 75

Abbreviations: PCOS, polycystic ovarian syndrome; OHSS, ovarian hyperstimulation syndrome; BMI, body mass index.

Abbreviations: PCOS, polycystic ovarian syndrome; OHSS, ovarian hyperstimulation syndrome; BMI, body mass index.

For this reason, we ask our patients to avoid unprotected sexual intercourse in the cycle where GnRH analog treatment begins. However, published data suggest that pregnancy outcome is not adversely affected by GnRH agonist administration in the luteal phase of the conception cycle (43). Luteal support is important in these patients to avoid early abortion.

Patient age and follicular-phase serum FSH values are two useful predictors of gonadotropin dosage. FSH starting dose for the different patient groups in our program are listed in Table 1. The duration and daily doses of FSH are adjusted according to individual patient age and response as judged by serum E2 levels and follicular number and size in an ultrasound scan of the ovary.

The National Collaborating Centre for Women's and Children's Health have reviewed ovarian monitoring during gonadotropin therapy for IVF. NICE found that serum estradiol monitoring provided no additional information compared with ovarian ultrasound and, therefore, do not recommend it. This is different to the above guidelines for basic ovarian stimulation and monitoring. We are comfortable with this contradiction. We consider that serum E2 measurement does assist inexperienced units towards effective multi-follicular ovulation induction. It also helps minimize ovarian hyperstimulation syndrome (OHSS). The above endocrinology guidelines may assist those units less experienced in IVF stimulation and monitoring.

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