Clinical Reproductive Endocrinology Stimulation Protocols

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The first IVF baby was born as a result of an oocyte picked up in a natural cycle. However, the success rate of this protocol was very low, and the Monash group first reported large numbers of eggs and improved pregnancy rates using a stimulation protocol of clomiphene citrate and human meno-pausal gonadotropin (HMG) together (32). Several other regimens using these two medicines were subsequently reported. The common problems with these protocols were that endogenous gonadotropins led to premature luteinization in 30-40% of the cases, and, in others, ovulation occurred at an inconvenient time of the day. The major step in simplifying IVF induction of ovulation protocols and preventing these unwanted phenomena came with the introduction of GnRH agonists. GnRH analogs were created by a series of modifications in the GnRH molecule that led to the availability of new agonists and antagonists. The agonists initially enhance gonadotropin released from the pituitary but, with continuing administration, caused downregulation of the pituitary and reduced LH and FSH secretion for as long as the analog was given. This effect was a powerful tool with which to control the stimulated IVF cycle. GnRH antagonists are now available for routine clinical use (see Chapter 5).

Initially, the use of GnRH agonists was confined to women with a history of unsatisfactory response to other stimulation protocols, a premature LH surge, or elevated plasma LH and FSH levels (33,34). There are now many reports advocating their use in all IVF cycles including those women with normal basal gonadotropins (35-37). Tan et al. (38) have reported life table analysis of conception and live birth rates in 3000 women undergoing IVF-ET with and without different regimens of the GnRH agonist busere-lin. They found that the cumulative conception rate and cumulative live birth rate were significantly higher in those patients treated with a downregulation regimen. The mechanism by which GnRH analogs improve follicular response is not yet known. Palermo et al. (34) reported improvement in synchronization of follicular development leading to a larger cohort of developing follicles, whereas others related it to the longer gonadotropin stimulation in the GnRH analog cycles.

Urinary gonadotropin preparation, HMG, which contains FSH and LH, was used since 1980 for ovarian stimulation for IVF (32). In 1991, a highly purified FSH preparation was introduced, suggesting that endogenous LH was sufficient for satisfactory folliculogenesis (39). A meta-analysis of randomized trials of FSH versus HMG performed on 599 patients indicated that the use of FSH was associated with a significantly higher clinical pregnancy rate than HMG (40).

Further meta-analyses by NICE have addressed cost-effective studies relating to gonadotropins. The National Collaborating Centre for Women's and Children's Health found that HMG, urinary FSH, and recombinant FSH were equally effective in achieving a live birth when used following pituitary downregulation as part of IVF treatment. NICE recommended that consideration should be given to minimizing cost when prescribing. In the United Kingdom, use of urinary FSH products could represent a potential cost saving of £15 million/year.

Typical protocols of ovarian stimulation in a typical IVF program are:

1. GnRH agonist/FSH—long downregulation protocol.

2. GnRH agonist/FSH—short ("boost" or "flare-up") protocol.

3. Clomiphene citrate/HMG.

The objective of the protocols is to obtain a cohort of codominant follicles in both ovaries with adequate E2 levels suitable for oocyte retrieval on days 11-15.

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