For Cancer Patients by Use of In Vitro Maturation and IVF
An important part of fertility treatment involving In Vitro Fertilization, employs Controlled Ovarian Stimulation (COH). A woman is born with all the eggs she will have in her lifetime and each month, from puberty to menopause, a genetically predetermined cohort of follicles gets “called up” from the remaining pool of immature eggs. In a natural cycle, under the influence of gonadotropin hormonal signals, usually just one of these follicles will reach full maturation, while the remainder will undergo atresia (cessation of development). With COH, exogenous gonadotropins are administered, to enable as many of the follicles which are “called up”, to reach full maturation. This enables the treating physician to harvest multiple eggs, for the purposes of generating multiple embryos, all with a view to improving pregnancy outcome.
The term IVM refers to the maturation in the laboratory, of immature eggs. After these immature eggs are recovered from follicles, that may or may not have been exposed to exogenous FSH but which were not exposed to either LH or HCG prior to retrieval, to induce meiotic resumption. This latter step, is important to increase the likelihood of obtaining usable oocytes. Even if an immature oocyte progresses to the MII (metaphase 2 or mature phase), complete competence of that egg is not necessarily obtained. This relates to dyssynchrony between nuclear and cytoplasmic maturation. So, even though an in vitro matured egg may look normal, it may not necessarily function normally. There are many reasons for this set of circumstances. In the literature, the definition of IVM has been expanded to include instances where COH is carried out but not to full completion, and in which eggs are in fact exposed to LH or HCG prior to retrieval. The final stages of egg maturation do take place in the laboratory.
Potential Applications of IVM
There are three broad groups of patients who may benefit from IVM. These include patients at risk for Ovarian Hyperstimulation Syndrome (OHSS); those with limited time for ovarian stimulation (e.g. patients with a malignancy where the oncologists are in a hurry to perform surgery or commence chemo and/or radiation therapy); and those with a contraindication to sustained elevations of estradiol ( e.g. history of hormone sensitive tumors). Since IVM either omits gonadotropins entirely, or uses a short course of gonadotropins, there is a reduction in the number of days of follicular monitoring, the amount of medication administered and the risk of OHSS. The risk of OHSS is especially important in patients with Polycystic Ovarian Syndrome (PCOS), because these patients have a large cohort of antral follicles which can mature under the influence of prolonged stimulation with gonadotropins. Although when first described, IVM was touted to significantly reduce cost of treatment, due to the need for less medication and less monitoring, cost savings alone should not drive the decision to move a patient to IVM, because pregnancy rates are not as good as with conventional IVF.
Although there are no randomized controlled trials comparing IVM with conventional IVF, there are a number of clinical studies using in vitro matured oocytes. Based on these reports, as well as our own experience, we have determined that a hybrid of using some gonadotropins, as well as administering HCG prior to egg retrieval, albeit when the follicles are not fully mature, yields the highest number of fertilizable eggs and embryos. The overall pregnancy rate in our series has been around 25%, which is lower than that expected with conventional IVF in similar aged patients, but still highly satisfactory given the complex nature of this patient population.
In our experience, so long as the follicle sizes are > 13 mm at the time of HCG administration, it is not necessary to change anything over conventional egg harvesting methods, including timing, needle size or diameter, or suction pressures. With follicle sizes of < 12 mm, egg yields have been quite disappointing. The in vitro management of less than mature eggs is however, quite different. We add pyruvic acid and other essential and non-essential amino acids, as well as using LH enriched culture media. Of critical importance, is that the embryologist manage eggs on an individualized basis, so as to maximize fertilization rates. What this means is that if the eggs are harvested at say noon, the embryologist should not decide that at 2.00 p.m. on the same day, that it is time for fertilization of the eggs and then try to inseminate all the eggs at the same time. Rather, the embryologist should individualize the timing of insemination of the eggs, based upon the morphological characteristics noted. This process can take several hours, or in some cases, span over the course of 1 – 3 days, as less than mature eggs, tend to mature in vitro on an individual basis, rather than all at once. It is our preference to use ICSI (intra-cytoplasmic sperm injection) to achieve fertilization, as experience has taught us that the zona pellucidae (outer shell) of immature eggs, can be quite impermeable to sperm.
We have consistently seen in vitro maturation rates of around 70% for eggs recovered from less than fully mature follicles. Fertilization rates have also approached 70% when only morphologically mature eggs have been inseminated with ICSI. Clinical pregnancy rates have been slightly lower than comparative aged patients, at around 25%. This may have something to do with endometrial synchronization, or alternatively, may be related to the complex nature of the underlying medical problems, necessitating IVM in the first place. The small number of children born from these procedures, limits the accuracy of the incidence of malformations but reassuringly, so far, they appear to be no different than in cases of conventional IVF.
Due to lower than expected pregnancy rates, IVM should not be used in all patients, but rather for a carefully selected group of patients. These include those at risk for OHSS, patients with hormone dependent tumors, or time constraints. In our experience, using a hybrid approach of gonadotropins and HCG administration at smaller follicle sizes, seems to maximize oocyte yield and fertilization rates. Individualization of laboratory management of the harvested eggs, can greatly improve fertilization and pregnancy rates. Until more data are available, we are not offering this approach as a first line treatment for all of our patients. However, IVM remains a useful alternative for a carefully selected subset of patients, as indicated.