NEWS AND VIEWS

In vitro Maturation (IVM) of human oocytes

Thomas Strowitzki

Published online: 26 September 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract In vitro maturation is a technique of assisted

reproduction which in contrast to standard IVF or ICSI

almost fully avoids hormonal stimulation. Immature

oocytes will be fully matured in vitro within 24 h after

oocyte collection. The method was introduced in the early

nineties and is indicated in patients at high risk for ovarian

hyperstimulation. Results are almost comparable to stan-

dard techniques. Up to now no elevated risk for fetal

malformations has been described. IVM is a suitable

alternative in IVF for an exactly defined subgroup of

patients, in particular patients with PCOS, but still does not

replace standard techniques.

Keywords In vitro maturation � Infertility �Assisted reproduction � PCOS

Definition

In vitro maturation (IVM) is an emerging technique in

assisted reproduction, which avoids classical controlled

ovarian hyperstimulation prior to ovum pickup for IVF/

ICSI. Although it has been introduced in clinical practice

already in the nineties, it is still far from being clinical

routine. In Germany, IVM is currently performed in one

university-based center only. Aim of this technique is the

collection of immature eggs from almost unstimulated

ovaries, followed by an IVM for 24 h until the extrusion of

the first polar body and consecutive insemination by stan-

dard IVF or ICSI.

Historical development of IVM

The history of IVM is surprisingly old. In the sixties of the

last century Robert G. Edwards has published some basic

data on IVM and reported the first successful fertilization

of in vitro matured oocytes in 1969 [1]. The first pregnancy

after IVM was reported by Cha et al. [2] in 1991, using

immature oocytes from ovaries removed for clinical rea-

sons. Trounson et al. [3] have used this technique in a

normal IVF/ICSI setting with transvaginal ovum pickup

followed by a pregnancy in 1994. In 2005, IVM programs

were successfully established in Germany in the centers of

the universities of Lubeck and Heidelberg.

Indications

Although some groups consider IVM as an ideal treatment

option for all IVF/ICSI indications, slowly replacing con-

trolled ovarian hyperstimulation, the technique is mainly

restricted to exactly defined indications. In particular,

women with a high risk of developing an ovarian hyper-

stimulation syndrome might benefit from this technique,

for example,

• women with PCOS

• women with a medical history of severe ovarian

hyperstimulation

• young women under the age of 30 years

Competitive to IVM, new stimulation protocols such as

low dose GnRH antagonist protocols and/or ovulation

T. Strowitzki (&)

Department of Gynecological Endocrinology and Fertility

Disorders, University Hospital Heidelberg, Im Neuenheimer

Feld 440, 69120 Heidelberg, Germany

e-mail: thomas_strowitzki@med.uni-heidelberg.de

123

Arch Gynecol Obstet (2013) 288:971–975

DOI 10.1007/s00404-013-3033-3

induction by GnRH analogs significantly reduced the

OHSS risk. Therefore, IVM might remain an option in

selected cases only. Women with PCOS are still an ideal

group for IVM, since their ovaries yield a high amount of

immature oocytes suitable for IVM.

Besides these standard indications, IVM might be used

also for patients with hypergonadotrophic hormonal status

due to FSH resistant ovaries and normal AMH and as

fertility preservation in patients with leucemia or in ovarian

endometriosis before removing endometriotic cysts [4].

This technique is one of the recommended treatment

modalities of the German network FertiProtekt.

In normo-ovulatory women, IVM does not reach success

rates of standard IVF/ICSI techniques and should no longer

be used [5].

Guzman et al. [6] have introduced a prediction model

for IVM and had looked at PCOS patients in non-HCG

triggered IVM cycles, minimally stimulated by gonado-

tropins. AMH, AFC, and testosterone might become

unrelated prognostic factors for the collection of oocytes.

The number of oocytes correlated further with the embryo

quality and the clinical pregnancy rate.

Minimal hormonal stimulation and oocyte collection

Pregnancy rates have risen during the last years and since

2009 they are almost comparable to standard stimulation

[7, 8]. The reason behind is a short-time low-dose priming

with 125 units recombinant FSH for 3 days starting

between day 3 and 7, followed by a single shot adminis-

tration of 250 lg recombinant HCG. This sort of a mild

priming has a positive impact on zona pellucida develop-

ment [9], the nuclear maturation of the oocytes [10] and

finally on the implantation rate [11]. Furthermore, priming

avoids the development of the dominance of a single fol-

licle which would potentially lead to atresia of small fol-

licles [12].

Follicular aspiration is time consuming compared to a

standard IVF. Therefore, short-time general anesthesia

should be preferred. The egg collection is performed via a

17G needle with a low-pressure aspiration.

In vitro maturation

After having identified the oocytes they will be matured for

24 h until extrusion of the first polar body. Using a mild

priming with FSH followed by HCG, some of these

oocytes show already expanded cumulus cells resulting in a

better embryonic quality [13]. HCG priming might lead to

an improved maturation rate although no difference in

consecutive pregnancy rates is described [14]. Matured

oocytes are fertilized by IVF or ICSI. In contrast to older

data fertilization rate is not inferior after IVF [9], hence

ICSI is no longer mandatory. If low dose FSH priming is

used ICSI does not offer any benefit and zona hardening is

not a major issue [9].

For culture, standardized commercial media are avail-

able supplemented with FSH, HCG and patient’s serum by

some groups.

Luteal phase support

Luteal phase support is absolutely needed in form of, for

example, 6 mg estradiol after oocytes’ collection supple-

mented with 600 mg progesterone to start the following

day. Endometrial maturation might be insufficient in IVM

cycle. That is why hormonal support should be continued

until pregnancy week 12.

Results of IVM

In theory, unnaturally accelerated maturation of oocytes

should have a negative impact on both, pregnancy rates and

malformation rates. Up to now this is not the case. Preg-

nancy rates per cycle of 17–24 % are reported, no elevated

malformation risk has been published (Table 1).

Published pregnancy rates are somewhat hard to com-

pare. In some studies, pregnancy rates are reported of truly

in vitro matured oocytes mixed with fully matured oocytes

due to the HCG priming [22]. This increases the pregnancy

rate from 23.3 % to around 40 %. If follicles of 14 mm are

punctured, pregnancy rates rise to 40.3 % [23].

Furthermore, numbers of transferred embryos differ

dramatically up to more than 4 embryos per cycle [18].

Buckett et al. [24] reported a higher early miscar-

riage rate after IVM in a retrospective study. However,

they could clearly demonstrate that the high miscarriage

rate is related to PCOS rather than the method used. Had

they compared PCOS patients only, no more difference

could have been detected between groups.

Endometrial maturation

Collecting immature oocytes without intensive hormonal

stimulation might simultaneously exert an insufficient

maturation of the endometrial development. Therefore,

IVM affords an endometrial supplementation by estrogen

and progesterone after the oocyte collection. Estrogen

should start 3 days before the oocyte pick up. Minimal

FSH stimulation is another option to correct an insufficient

endometrium.

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IVM and standard IVF/ICSI—pros and cons

Studies in favor of IVM compared to standard IVF proto-

cols in PCOS patients rise constantly. IVM should be at

least equally effective as IVF in GnRH agonist or antag-

onist protocols [7]. Although number of oocytes and

embryos was lower, live birth rate per embryo transfer was

fully comparable. In PCOS patients, IVM might yield an

even higher number of oocytes with similar pregnancy

rates [25]. However, these results are not confirmed by

other groups; for example, in a case–control study by

Gremeau and coworkers [26] IVF led to a significantly

higher implantation, pregnancy and live birth rate.

The undisputable advantage of IVM is the complete

avoidance of the ovarian hyperstimulation syndrome

(OHSS). Second, the technique allows short-time treatment

without delay, which might be necessary in fertility pro-

tection prior to anti-cancer chemotherapy. Costs are lower,

but efficiency might be lower as well. Transvaginal egg

collection is time consuming and needs long experience to

collect a sufficient number of oocytes.

In the laboratory, biologists need more time with IVM

than with standard techniques. Special culture media fur-

ther rise laboratory costs.

Longtime sequelae of IVM

In vitro maturation is still a somehow young clinical

method with limited experience of the longtime outcome of

children. Accelerating oocyte maturation might theoreti-

cally negatively affect children’s development. Up to now,

there is no higher risk for chromosomal aberrations

reported [27]. Furthermore, unphysiological culture con-

dition depleted of an intact follicular environment might

bear a risk for failure of genetic reprogramming and

imprinting defects.

Data of children’s development after IVM are limited.

Scientists did not describe a higher malformation rate [11,

16, 28]. A retrospective analysis by Buckett et al. [29]

calculated an odds ratio for malformations compared to

spontaneous conception of 1.42 in IVM cycles, 1.21 in

IVF, and 1.69 in ICSI. Mental development of IVM chil-

dren also showed no differences [30] and neuropsycho-

logical evaluation after 2 years is normal [31]. In our study,

we also saw no IVM-related abnormalities [21].

Conclusion

In vitro maturation is a special technique suitable for a

clearly defined group of patients, in particular PCOS. It

fully avoids the risk of ovarian hyperstimulation, but

results are still slightly inferior to standard IVF/ICSI pro-

tocols. Mild forms of hormonal stimulation might be an

effective alternative to IVM even in patients at risk. Data of

children’s long time outcome are still limited and needs

further approval.

Conflict of interest None.

References

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Table 1 Clinical results of

IVM [15]IVM

cycles

Aspirated

oocytes

Matured

oocytes (%)

Fertilized

oocytes

Preg. rate/

cycle

Cha et al. [16] 94 13.6 62 5.1 (68 %) 23 (24 %)

Child et al. [17] 107 10.3 75 6.1 (78 %) 23 (21 %)

Chian et al. [18] 254 11.9 79 5.9 (69 %) 61 (24 %)

Le Du et al. [19] 45 11.4 63 4.9 (70 %) 9 (20 %)

Benkhalifa et al. [20] 350 9 62 – 15.2 %

Roesner et al. [21] 215 8.9 64 2.8 27 (15.3 %)

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New Associate Editor: Prof. Thomas Strowitzki

From 1983 until 1984, he had begun his residentship in Gynecology and Obstetrics at the University of the Saarland.

Since September 1984, he continued his work at the Department of Obstetrics and Gynecology, Klinikum

Grosshadern, University of Munich. Strowitzki gained his board certification in 1991 and the subspecialty in

Gynecological Endocrinology and Reproductive Medicine in 1995. He finished his habilitation with a project on

IGF and IGFBP in the human endometrium in 1995 and gained a professorship at the Department of Obstetrics and

Gynecology, Klinikum Grosshadern, University of Munich in 1998. In 1999, he took a professorship at the

University of Heidelberg and since then he is medical director of the Department of Gynecological Endocrinology

and Reproductive Medicine at the University of Heidelberg. His scientific interest is primarily endometrial

differentiation and implantation, the polycystic ovary syndrome and reproductive medicine in particular on IVM,

currently funded by a FOR of the DFG. He received the Ludwig Fraenkel award of the German Society for

Obstetrics and Gynecology in 1994, the honor medal of the Medical Faculty of the University of Heidelberg in 2012.

He is a reviewer for all leading journals in the field of reproductive medicine and editor and co-editor of several

journals like ‘‘Gynakologische Endokrinologie’’ and ‘‘Der Gynakologe’’. Besides his medical interest in gynecological

endocrinology and reproductive medicine, Strowitzki serves as the head of the Ethical Committee Medical Faculty,

University of Heidelberg and is a member of several highly respected expert commissions, for example, for the

National Academy of Science Leopoldina.

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