Presentation in early follicular phase can very similarly be treated like convention stimulation regimens with GnRH antagonist protocol provided there is no dominant follicle more than 12 mm. If there is already dominant follicle more than 12 mm, it can then be treated as being in late follicular phase, which will be discussed subsequently (Fig. 33.1).

Late follicular ovarian stimulation involves assessment of the ovaries for the presence or absence of dominant follicles. If the ovary contains dominant follicle more than 12 mm, further management would involve luteolysis of the dominant follicle with either GnRH antagonist or progesterone followed by stimulation for the rest of the follicles. Prior to luteolysis, triggering of the already grown follicle by HCG or GnRH agonist may be considered. This can then be followed 36–40 h later by luteolysis with GnRH antagonist for 3–4 days. Depending on the ovarian reserve of the patient, ovarian stimulation can then be started by appropriate gonadotropins based on age and ovarian reserve parameters (AMH, antral follicular count) (Fig. 33.1).

Early luteal phase is defined as the completion of spontaneous LH surge and the presence of corpus luteum in the ovaries. Early and late luteal phase can be essentially treated in the same way. Luteolysis of the corpus luteum can be achieved by GnRH antagonist 3 mg stat or in multiple doses of 0.25 mg. This can be followed by gonadotropin stimulation in conventional way preferably with recombinant FSH avoiding exogenous LH activity, which might prevent luteolysis. Pituitary suppression for LH surge by GnRH antagonist can be initiated in usual way when the dominant follicle reaches 14 mm and use of either HCG or GnRH agonist for trigger of the final maturation of the oocyte. (Fig. 33.1)

The dose of gonadotropin should be individualized depending on age, ovarian reserve, and weight of the patient. Using higher doses of gonadotropins can be one of the strategies to increase the embryo and oocyte yield per cycle. In a study comparing a low-dose antagonist IVF protocol (150 IU FSH) and a higher-dose antagonist IVF protocol (>150 UI) in cancer patients, although the number of follicles > 17 mm was greater in the higher-dose group, there was no difference in the number of oocytes generated between the two groups [10]. That study suggests that the use of higher doses of gonadotropins may not necessarily result in higher oocyte/embryo yield consistent with the theory that higher doses of gonadotropins may stimulate the recruitment of chromosomally abnormal or incompetent oocytes [11]. However, in patients with decreased ovarian reserve as assessed with the use of AFC and/or AMH, higher doses of gonadotropins may be required.

The studies have suggested that these protocols have been able to provide reasonable number of mature eggs able to fertilize but the exact implantation potential and subsequent pregnancy rates of embryos and oocytes retrieved through these protocols are still unanswered. Being relatively new and being tried mainly in cases in cancer patients, these have been reported in very few studies.

Controlled ovarian stimulation in women with estrogen-sensitive tumors is another challenge and should be dealt with caution. This can be achieved with addition of letrozole or tamoxifen to the above protocols to nullify the effect of rising estradiol levels during stimulation. Study by Oktay et al. [12] concluded that stimulation protocols using letrozole alongside gonadotropins are currently preferred over tamoxifen protocols as treatment with letrozole results in a higher number of oocytes obtained and fertilized when compared to tamoxifen protocols.

There has been case report by Reichamn et al. [13] of using these ovarian stimulation protocols for oocyte vitrification in prepubertal girls diagnosed with cancer that have not yet attained menarche and hence got no gonadotropin recruitable follicles. This has been reported as having successful ovarian stimulation and oocyte retrieval. This approach needs further robust evidence before it can be widely applicable to such group of cancer-affected females.

The goal of superovulation for this group of patients represents a compromise between obtaining a relatively large number of oocytes for vitrification, to maximize chances of later pregnancy, and the absolute need for avoidance of ovarian hyperstimulation in a patient who will shortly begin chemotherapy.

The patients referred for fertility preservation may not necessarily represent the typical population of subfertile patients treated in IVF units. Cancer may affect multiple tissues throughout the body and can result in variety of complications during ovarian stimulation. Cancer may induce hypercoagulable state, and when this is combined with increased serum estradiol levels, it may put cancer patients undergoing controlled ovarian stimulation at an increased risk of thromboembolic events. Therefore, consideration should be given for commencement of anticoagulation therapy around the time of ovarian stimulation. The other strategy of preventing thromboembolic events is to use letrozole during ovarian stimulation as in women undergoing ovarian stimulation with estrogen-sensitive malignancies to keep estradiol levels close to <500 pg/ml. Letrozole at 2.5 or 5 mg/day can be started with ovarian stimulation and can be titrated up to 10 mg/day depending on the estradiol levels. Letrozole or GnRH antagonist should be continued even after oocyte retrieval for up to a week depending on the estradiol levels at the time of ovulation induction.