Milder is better? advantages and disadvantages of "mild" ovarian stimulation for human in vitro fertilization

Abstract

In the last decades, several steps have been made aiming at rendering human IVF more successful on one side, more tolerable on the other side. The "mild" ovarian stimulation approach, in which a lower-than-average dose of exogenous gonadotropins is given and gonadotropin treatment is started from day 2 to 7 of the cycle, represents a significant step toward a more patient's friendly IVF. However, a clear view of its virtues and defects is still lacking, because only a few prospective randomized trials comparing "mild" vs. conventional stimulation exist, and they do not consider some important aspects, such as, e.g., thawing cycles. This review gives a complete panorama of the "mild" stimulation philosophy, showing its advantages vs. conventional ovarian stimulation, but also discussing its disadvantages. Both patients with a normal ovarian responsiveness to exogenous gonadotropins and women with a poor ovarian reserve are considered. Overall, we conclude that the level of evidence supporting the use of "mild" stimulation protocols is still rather poor, and further, properly powered prospective studies about "mild" treatment regimens are required.

MILD ovarian stimulation with GnRH-antagonist vs. long protocol with low dose FSH for non-PCO high responders undergoing IVF: a prospective, randomized study including thawing cycles

“…Some published reports compared the effectiveness of "mild" and "long" stimulation regimens in women with good ovarian reserve [9][10][11]. Taken singularly, all three RCTs found comparable results in terms of IVF effectiveness; however, if their results are pooled togetherreaching a total number of 592 fresh IVF cycles, 313 performed with the "mild" regimen and 279 with the "long" regimen-it may be seen that relevantly poorer results were obtained with the "mild" protocol [12]. In addition, none of the three RCTs included freeze-thaw cycles, that relevantly contribute to the overall cumulative pregnancy rate; theorically, the "mild" approach should produce less oocytes and embryos available for freezing than the "classical" one, and therefore the inclusion of thawing cycles could widen the gap in favour of the "classical" strategy.…”

“…Unfortunately, however, pooling together the results of these RCTs, a noticeably lower effectiveness of the "mild" strategy appeared [12]. These RCTs [9][10][11], moreover, did not include the results deriving from frozen/thawed material (embryos and/or oocytes), a lack that did not allow to properly estimate the relative effectiveness of the two different stimulation approaches.…”

“Mild” vs. “long” protocol for controlled ovarian hyperstimulation in patients with expected poor ovarian responsiveness undergoing in vitro fertilization (IVF): a large prospective randomized trial

“…anti-estrogens) are used either alone or in combination with Gn and GnRH-antagonists [9]. The "mild" protocols have a softer impact on the ovary, are better tolerated, imply a much lower risks, are quicker and cheaper as less medications are used for a shorter time [10,11]. On the other side, the "mild" stimulation strategy leads to the retrieval of less oocytes, a reason for which it has been proposed mainly for young, good responding patients [10,11].…”

Efficacy and safety of late-start Corifollitropin-alfa administration for controlled ovarian hyperstimulation in IVF: a cohort, case–control study

“…The late-start, "mild" stimulation COS regimens are subjectively better tolerated (less abdominal discomfort and swelling) (15), shorter, and consequently probably cheaper than standard protocols (2,3,17). In comparison to the "classical" COS, they compensate the slightly reduced "per attempt" effectiveness with the improved tolerability, that lowers the drop-out rate and finally increases the number of attempts, leading to a comparable cumulative yearly success rate (18).…”

“…Further, GnRH-antagonists allowed to develop the so-called "mild" or "minimal" stimulation COS regimens, in which the initial follicular recruitment is accomplished by endogenous gonadotropins, and exogenous Gn are administered only from day 4-5 of the cycle onward (1)(2)(3)(4). Aim of the "mild" COS is to obtain a patient-friendly treatment, with higher tolerability and without worsening IVF outcome.…”