In vitro maturation (IVM) of oocytes
What exactly is IVM?
It is a technique used in the context of medically assisted procreation. It consists in collecting immature oocytes from the ovaries and “maturing” them artificially outside of the body, in vitro, in a laboratory.
The first baby born from this technique in 1991 was born in Korea. Several teams are working on the subject worldwide. In Vietnam, in Belgium, in the United States etc.
In 2019 in France, the birth of twins through that technique to a 35-year6old woman suffering from ovarian auto-immune deficiency (i.e. premature menopause) was announced as a world first.
What is the purpose of the technique?
The purpose of the IVM techniques is to reduce the need for resorting to hormones. Therefore, avoiding the use of ovarian stimulation, by hormone injections, intended to maximise the probability of collecting several oocytes during collection. These in fact involve a risk of discomfort and sometimes serious side-effects. Ovarian stimulation is not recommended for certain women. IVM techniques would be particularly recommended for women suffering from a polycystic ovary syndrome, where there is a risk of developing a serious hyperstimulation which can be life-threatening.
The collection of oocytes is conducted in two situations: either when an ART process with in vitro fertilisation (IVF) is undertaken. Or when it is intended to proceed with cryogenic preservation of oocytes. The preservation of oocytes is used either for medical reasons (for example before undergoing a heavy chemotherapy type treatment) or for reasons of personal convenience (made possible in France by the 2021 bioethics law for women between 29 and 37 years of age).
In certain states, where the “sale” of gametes is not prohibited, certain women choose to have their oocytes collected for financial reward. The market exists, it is fed by the demand of women who have procreation difficulties and by the practice of surrogate motherhood where, routinely, the sponsor resorts to purchasing oocytes, and contracts a surrogate mother. The market of oocytes is also fed by research needs.
What is meant by the “maturing” of oocytes?
The natural production of oocytes within the woman’s ovary is a very long and complex process which initiates for young girls when they are still in the womb. If a cell manages to achieve a “complete cycle” it will have started during the first month of pregnancy, by the appearance of germinal cells, and concludes with its fertilisation, which “completes” its maturation and constitutes an ovum.
These various stages of maturation constitute what is known as meiosis, and result in cells which do not have 46 chromosomes, like the rest of the cells in the body, but have only 23. It is the particularity of gametes: to contain only 23 chromosomes, so that during fertilisation, the fusion with a cell of the other sex, will lead to the conception of a zygote, which is the first cell of the new individual consisting of 46 chromosomes, 23 from the father and 23 from the mother.
I oocytes develop during the first months of pregnancy. These cells still have 46 chromosomes. This is known as the follicular stock. It is not regenerated, and constantly diminishes, as early as life in the womb. At puberty, the “stock” of follicles will be approximately a mere 400,000 follicles. Among those, only 400 will reach maturity and result in ovulation, during the period between puberty and menopause.
During the female menstrual cycle, at ovulation (expulsion from the ovary), an oocyte I (sometimes several) per cycle resume their meiosis division. This maturation process leads to a II oocyte, consisting of 23 chromosomes.
This maturation process linked to ovulation occurs in connection with the entire microenvironment present in the young woman. The maturation occurs in response to complex signals, regulated timewise, through the effect of hormones, growth factors and in a dynamic associated with the presence of nutriments within the follicular environment. Many of these processes are regulated by the ovarian cells.
This slow maturation is aimed at a rapid growth of the cell; it constitutes a “preparation” for a possible fertilisation. The oocyte II contains half of the genetic material which contributes to the future zygote after fertilisation, but also the mitochondrial genome and the overall cytoplasm of the future zygote. This cytoplasm contains the necessary energy reserves for the development of the future embryo.
How can one artificially mature the oocytes?
Gameto, a biotechnology company based in Texas, uses induced pluripotent stem cells (IPS), their “ovarian support cell (OSC) technology” is called Fertilo. Gameto has just announced obtaining authorisation from the Food and Drug Administration (FDA) to perform a first phase 3 clinical test. The authorisation follows the first birth of a child conceived using the Fertilo technology, in a clinic in Lima, Peru, in December 2024. The clinical test will be conducted in 15 sites in the United States. It will evaluate the rate of pregnancies (as a measure of efficiency), the development of the embryo, the maternal health and the rate of live births (as harmless criteria).
Its inventers highlight the fact that only 3 days of stimulation are necessary, compared with the usual 2 weeks with the so-called conventional IVF.
In order to mature the oocytes artificially outside of the body, Fertilo recreates an ovarian environment and makes use of co-culture of immature oocytes with ovarian support cells (OSC) obtained by the so-called IPS reprogramming technique. According to its inventor, Fertilo mimics a young ovarian environment, reproducing the natural body maturing process by satisfying the needs of the ova and producing the necessary nutriment hormones. In simple terms: the technique consists in artificially producing a medium which simulates the conditions of an ovary, and contains cells capable of synthesising what the oocytes require for maturation.
An immense market
These new techniques have an immense growth potential. Gameto has been granted regulatory authorisation for Japan, Argentina, Paraguay, Mexico and Peru. The company has also announced a partnership with IVFAustralia.
A priority research theme in France
Restoration of fertility by in vitro and in vivo maturation (tissue grafts or germinal cell transplant) are among the priority research themes identified by the “Fertility restoration” working group through the report issued to the Government in 2022 (Report on the causes of infertility – Search for a national strategy to combat infertility).
Limits and ethical stakes
Studies have shown mixed results in terms of maturation rates of oocytes, embryo formation, and certain studies have shown lower pregnancy rates than those obtained by conventional IVF. In truth, it is extremely complicated to establish a satisfactory “degree of maturation” for oocytes.
The authors of a fundamental research study consider that an important validation of the clinical utility will be the “ability to generate healthy live births”.
There lies a fundamental question: that of the impact on the health of the children to be born. In addition to questions on the ethical stakes associated with artificial procreation techniques (the consumption of embryos, disconnections between union and procreation, between procreation and pregnancy, supernumerary embryos etc.), there are also sanitary stakes. The oocyte is the cell which constitutes the zygote, once fertilisation is complete. That cell acts as the “base” for the construction of the new individual. It is difficult to evaluate the innocuousness of techniques which do not allow true prior tests but which treat each child born as a “life-size” test of the technique which contributed to its conception and its birth.
