Conventional ovarian stimulation protocols for IVF are designed to achieve maximum oocyte yields. Conventional protocols, however, are associated with patient discomfort, increased risk of ovarian hyperstimulation syndrome and higher costs. In recent years, mild stimulation protocols have risen in popularity. These protocols typically use lower doses (≤150 IU/day), shorter duration of exogenous gonadotrophins, or both, compared with conventional protocols, with the goal of limiting the number of retrieved oocytes to less than eight. The pregnancy rate per cycle (fresh embryo transfer only) is lower with mild stimulation compared with conventional stimulation; however, the cumulative pregnancy rate seems to be comparable between the approaches. Reports are conflicting on the effects of mild versus conventional stimulation on embryo quality.

The most commonly used gonadotrophins in controlled ovarian stimulation protocols are highly purified urinary HMG and rFSH. The administration of exogenous gonadotro- phins maintains FSH and LH levels above a critical threshold needed to stimulate the development of many follicles, thus allowing the re- trieval of multiple oocytes in a single IVF cycle. Concomitant administration of a GnRH agonist or antagonist is used to prevent a premature LH surge, which may occur with the devel- opment of multiple dominant follicles. Final oocyte maturation and ovulation is typically triggered with a bolus of GnRH agonist, HCG (a hormone that is biologically similar to LH but has a longer half- life), or both.

Table 1 – Advantages and disadvantages of conventional and mild stimulation protocols.



Maximizes the number of oocytes retrieved
Greater number of embryos for cryopreservation
May help patients complete their family in fewer stimulated cycles Higher pregnancy rates per cycle

Greater patient discomfort and increased risk of complications, including OHSSa
Increased per-cycle costs associated with higher gonadotrophin dosage Higher per-cycle drop-out rates



Minimizes treatment burden and reduces risk of complications Lower doses of gonadotrophins and fewer injections
Possible association with better embryo quality
Lower per-cycle drop-out rates


Higher per-cycle cancellation rate; may require multiple stimulated cycles to achieve a pregnancy

Few embryos available for cryopreservation
Increased cumulative costs associated with multiple fresh cycles

a When used with a traditional HCG trigger. OHSS, ovarian hyperstimulation syndrome.



GnRH agonist and antagonist protocols utilize agonistic or antagonistic analogues of GnRH. GnRH analogues are decapeptides designed after human GnRH in order to interact with GnRH receptors. These analogues have certain amino acids substitutions in the gonadotropin amino acid sequence that increases the half-lives and competencies of analogues compared to natural hormones. GnRH agonists allows sustained stimulation of gonadotropin secretion, while GnRH antagonists act as mediators of chemical hypophysectomy. Overall, both analogues are widely used in IVF to induce folliculogenesis via prevention of endogenous LH surge and timed oocyte retrieval. Several agonistic analogues (triptorelin, leuprorelin, deslorelin, goserelin and nafarelin) and a couple antagonistic analogues (cetrorelix and ganirelix) have been introduced into clinical practices . Among the various GnRH agonist long protocols, namely ultra short, short and long, the long GnRH agonist protocol has been used as the gold standard in IVF since its discovery in the 1980s. The recent development of GnRH antagonists has offered an alternative approach in IVF treatment.












The main goal of COH is to obtain a greater numbers of mature follicles by suppressing the premature LH surge. GnRH agonist long protocol achieves a higher number of mature follicles compared to the other protocols. The use of high doses of gonadotropin and longer duration of treatment in this protocol has made many physicians to opt for other options such the antagonist and/or minimal stimulation protocols. However, GnRH agonist long protocol undoubtedly offers advantages of higher number of oocytes and viable embryos, which can be cryopreserved and used for frozen embryo transfer with better outcomes in patients with extreme BMIs and advanced age.

The minimal stimulation protocol using CC and gonadotropin is an attractive option considering its lower cost and gonadotropin ampoules as well as similar pregnancy and transplantation rates to GnRH agonist protocol. This protocol also limits the daily monitoring visits and ultrasonography compared to the standard protocol; hence this protocol can be considered a better option in patients with poor ovarian reserve and poor responders. Nevertheless, this protocol has the major disadvantage of decreased follicular development for patients with normal ovarian function.

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