Ovarian stimulation treatment aims to induce or improve oocyte maturation through hormone treatment or hormonal stimulation (see also under Medication). This is done with tablets or with injections, which the woman - depending on the instructions - can inject herself into the subcutaneous fatty tissue. The effect of this hormone treatment is monitored with ultrasound examinations and hormone determinations in the blood.
It can induce pregnancy even before assisted reproductive techniques are used.
First half of the cycle (approx. 1st-14th day)
For more information, see "Cycle & fertilisation".
In intrauterine insemination, previously selected sperm from the partner are introduced into the uterine cavity using a thin cannula. It is a simple treatment with few side effects. The chances of success are limited. In contrast to earlier assumptions, several large international studies unfortunately show very limited pregnancy rates, even with additional ovarian stimulation - well below 10% per treatment cycle. If there are no other limitations in both partners, then this procedure is only useful for very few indications - ejaculation and erectile dysfunction, anatomically severe cervical factor, use of donor sperm, etc. In view of the low success rate, patients should not be older than 35 years and the desire to have children should not date back significantly more than one to two years.
Exploiting the effect of hormones
In the first step of intrauterine insemination, several follicles are brought to maturation by controlled hyperstimulation. A number of further steps follow.
If there is a complete absence of sperm from the partner, e.g. as a result of illness, surgery or radiotherapy, intrauterine insemination can also be performed with donor sperm (so-called heterologous insemination). We will be happy to advise you about this possibility.
For intrauterine insemination, several follicles
must be brought to maturation by hyperstimulation with the drugs clomiphene, FSH or HMG.
By ultrasound and blood test
At the beginning of the treatment we examine by ultrasound whether everything is in order. During the stimulation treatment, the growing follicles are also checked by ultrasound. In parallel, we measure the hormone estradiol (E2) in the blood, possibly also LH and progesterone.
Preparation for insemination
As soon as the hormone and ultrasound tests show the appropriate values, we trigger ovulation by injecting hCG (instead of natural LH).
Getting the sperm to the laboratory
quickly and germ-free It is crucial that the sperm is germ-free on the day of fertilisation two hours before the partner's appointment. It can also be obtained at home - but must then be brought immediately to our laboratory. There, the sperm is cleaned and concentrated using special processing methods (gradient centrifugation-swim-up method).
Ensuring sperm quality
We select the optimal sperm and prepare the sperm sample for insemination.
Transfer of sperm into the uterine cavity
At the time of ovulation, we transfer the specially prepared "washed" partner sperm (so-called homologous insemination) directly into the uterine cavity using a syringe and a thin catheter. Insemination is mainly used in cases of slightly reduced male fertility. The same applies to abnormalities in the area of the cervix, which hinder the ascent of sperm into the uterine cavity.
In-vitro fertilisation is fertilisation in a test tube (in-vitro = in a glass). For this purpose, oocytes capable of being fertilised are removed from the woman, placed in a nutrient solution in the laboratory and fertilised with the partner's sperm cells. We transfer the fertilised oocytes or embryos back into the uterine cavity.
Since the first "test-tube baby" in 1978, this type of artificial insemination has been constantly developed and refined. This has significantly increased the chances of success for pregnancy.
Retrieval and fertilisation of multiple oocytes
Through controlled hormonal hyperstimulation, we increase the chances of retrieving multiple oocytes to successfully fertilise them and transfer one to three embryos into the uterus. Hormonal stimulation with genetically engineered FSH or HMG has proven successful. To prevent premature ovulation, FSH or HMG stimulation is combined with a GnRH agonist or antagonist.
By ultrasound and blood test
During the stimulation treatment we check the growing follicles by ultrasound. In parallel, we measure the hormone estradiol (E2) in the blood, possibly also LH and progesterone. In this way, we determine the most favourable time for obtaining mature oocytes capable of fertilisation.
Timely oocyte retrieval
When the most appropriate time for oocyte retrieval has arrived, we induce ovulation by injecting hCG so that the oocytes can be retrieved from the follicle after about 36 hours. 40 hours later ovulation would occur, so the oocytes would be lost.
Outpatient procedure under anaesthesia
The puncture of the follicle for oocyte collection is performed from the vagina using ultrasound. A general anaesthetic is not absolutely necessary, but makes the procedure much more comfortable. In addition, sufficient oocytes can then be obtained even under difficult puncture conditions. If there are no complications, you can go home the same day.
Fast and germ-free to the laboratory
After the oocyte collection, the sperm must be collected within four hours. This can also be done at home if it is brought to our laboratory immediately afterwards. There, the sperm is cleaned and concentrated using special processing methods (density gradient centrifugation).
If the sperm count is particularly limited, other processing methods can be used in addition to the ICSI procedure.
If there is a complete absence of sperm from the partner, e.g. as a result of illness, surgery or radiotherapy, in-vitro fertilisation can also be performed using donor sperm. We will be happy to advise you about this possibility.
Union of sperm and oocytes
After two to six hours, the prepared motile sperm are added to the oocytes in the culture fluid. Conventional in-vitro fertilisation requires 250,000 motile sperm per oocyte. In most cases, the oocyte and sperm cells remain in the warming cabinet at 37° C for about 24 hours. Subsequently, it is checked whether sperm have penetrated the oocyte and whether fertilisation has taken place (impregnation).
Maturation in the incubator
We select two to three impregnated oocytes and cultivate them for one to two days in the incubator. Excess impregnated oocytes can be frozen and used at a later date. During incubation in the warming cabinet, the fertilised oocytes divide. We transfer them into the uterus as four- or eight-celled embryos.
The fertilised oocytes develop into embryos through cell division:
Falling behind in this developmental dynamic marks a possible defect in the embryo with the inability to develop further and implant. Only about 30% of the pronuclear stages reach the blastocyst stage.
We raise one to three selected embryos in a thin catheter and insert them into the uterus. Normally we transfer 1-2 oocytes per cycle.
Opportunity: The younger the woman, the better
The natural pregnancy rate is 20 to 25% per cycle, depending on age. In 2018, the pregnancy rate per embryo transfer in our country was 42.9% per embryo transfer for IVF+ICSI at first treatment in women up to 40 years of age. After up to three treatment cycles, 76.9% of women are pregnant. The age of the woman has a significant impact on the chances of success.
The pregnancy rate per embryo transfer with IVF+ICSI in the first treatment in women up to 40 years of age is 44.6%.
After up to four treatment cycles, 83.5% of women are pregnant. The age of the woman has a significant impact on the chances of success.
Overstimulation can cause side effects - but these are treatable
Like any physical procedure, in-vitro fertilisation carries risks. The aim of hormone treatment is the maturation of several oocytes. Despite careful ultrasound and serum hormone monitoring, overstimulation may occur. The so-called overstimulation syndrome is associated with a marked enlargement of the ovaries, abdominal pain and relatively high oestrogen levels, which lead to increased vascular permeability and thereby to a raised risk of thrombosis. However, these symptoms are easily treated and disappear completely. During pre-diagnosis for IVF, patients with a high risk of hyperstimulation are identified. Overstimulation can be largely avoided by individually adapted stimulation.
To increase the chances of success of the IVF procedure, two or a maximum of three embryos are usually transferred. This increases the multiple birth rate compared to the normal multiple birth rate: Out of 100 births after ICSI, 20.01 percent are twin births and 0.8 percent are triplet births (German IVF Registry 2017). This compares to a natural frequency of 1.2 percent twin births and 0.013 percent triplet births. Usually only 1 to 2 and in a few cases 3 embryos are transferred.
Deformities in the child cannot be excluded in any pregnancy. The debate over whether children conceived after the use of IVF or ICSI have a raised risk of malformations is ongoing. However, the figures show that the slightly increased risk compared to naturally conceived children is not due to the methods, but mainly to the genetic and personal conditions of the parents with fertility problems.
A percentage increase in risk may occur if the couple introduces additional individual characteristics, such as:
Further information can also be found at www.repromed.de.
Time and again, fertility-enhancing drugs have been linked to a raised risk of cancer. There is no evidence for this.
Clomiphene - stimulates oocyte maturation
Clomiphene is mainly used before simple therapeutic interventions, e.g. before ovarian stimulation with or without insemination. Clomiphene leads to a raised release of GnRH, the gonadotropin-releasing hormone, in the hypothalamus. This causes a significant increase in FSH, the follicle-stimulating hormone, in the pituitary gland - stimulating oocyte maturation in the ovary.
The preparation is taken as a tablet. In isolated cases, hot flushes, sweating, dizziness and visual disturbances have been reported. However, these side effects usually disappear immediately after stopping the drug. However, depending on the dose, one or more oocytes may mature - occasionally resulting in twin and very rarely triplet pregnancies.
Proteohormones (FSH, LH, HMG, HCG) - stimulate the ovaries
Follicle Stimulating Hormone (FSH) is the main hormone used to stimulate the ovaries. It is used in all standard in-vitro fertilisation protocols. In addition, luteinising hormone (LH) may be required in special cases. Both hormones are produced using genetic engineering.
HMG is a purified hormone preparation obtained from urine, which contains a defined amount of FSH in addition to a proportion of foreign proteins. It is used as an alternative to genetically engineered FSH.
HCG is the so-called pregnancy hormone, which is also available in a genetically engineered form as well as in a form purified from urine. In the context of fertility treatment, it is used to induce ovulation and support the luteal phase due to its similarity to LH.
All proteohormones are administered as injections under the skin - usually by the patients themselves.
Progesterone - promotes embryo implantation
Progesterone is produced by the ovaries in the second half of the cycle after ovulation. It affects the formation of decidua cells in the lining of the uterus, which allow embryos to implant. To ensure that there is enough progesterone in the uterus, progesterone capsules or a progesterone gel to be inserted into the vagina are prescribed during IVF treatment after oocyte retrieval. The use of these drugs is intended until the pregnancy test after two weeks and if it is positive, beyond that.
These substances make the cycle even more controllable. This can trigger ovulation to the exact day. GnRH analogues and GnRH antagonists block the pituitary gland and thereby prevent premature ovulation.
GnRH analogues are effective after a two-week lead time.
Thereafter, external ovarian stimulation by administration of FSH or HMG begins. This lasts about nine to 14 days. During this time you will continue to take GnRH analogues - as an injection or nasal spray.
GnRH antagonists work immediately
They are only used during ongoing stimulation - until ovulation is triggered. GnRH antagonists must be injected.
We will discuss together which of the two treatment methods is best for you.
TESE stands for testicular sperm extraction and refers to the extraction of sperm from removed testicular tissue prior to ICSI treatment. The operation is performed either at the same time as the oocyte collection or - often better - in advance of the ICSI treatment. The tissue sample or the extracted sperm are frozen (cryopreservation) so that they can be used for fertility treatment if required.
What is the cause of sperm-depleted ejaculate?
This question is answered by a fine-tissue diagnosis (histology) of the tissue sample obtained. In addition, testicular diseases can be detected or excluded.
All necessary disciplines under one roof
Such a complex treatment requires close cooperation between gynaecology and urology. In many cases it is also useful to consult an experienced human geneticist. With us you will find all specialist disciplines under one roof, which favours an optimal course of treatment.
When an embryo develops from an oocyte into a blastocyst, it is surrounded by a shell - the zona pellucida. This shell protects it until shortly before implantation in the uterus. Then special enzymes and the embryonic growth pressure cause the zona pellucida to break open and the embryo to hatch.
The background for the development of assisted hatching
is the assumption that this envelope hardens through in-vitro cultivation or cryopreservation. Today it is the safest method for partial thinning of the zona pellucida. However, their clinical significance is currently not fully understood.
Depending on the age of the woman, 20 to 70% of the oocytes show genetic anomalies. In most cases, these oocytes - or the resulting embryos - are not capable of development, or are only capable of development for a short time. In polar body diagnostics, the oocyte retrieved for artificial insemination is examined before it is fused with the paternal pronucleus. Since there is an identical image of the chromosomes in the polar bodies, it is possible to detect a maldistribution (aneuploidy) of individual chromosomes.
However, this method of increasing the efficiency of in-vitro fertilisation is controversial. Damage to embryos or oocytes cannot be completely ruled out either. The complexity of this diagnostic procedure and the narrow time window can lead to false positive or false negative findings.
Embryos can be cultured until the fifth or sixth day after oocyte collection to better identify the embryo's developmental potential. Since this increases the chance of pregnancy, fewer embryos can be transferred. This reduces the risk of a higher grade multiple pregnancy - without reducing the likelihood of pregnancy.
Using "time-lapse videomorphokinetics" (see also embryoscope) it is now possible to observe embryos continuously during their early development.
This enables us to recognise the embryo's potential even earlier and more reliably, so that we can transfer it to the uterus after just three days - and eliminate the possible disadvantages of a longer embryo culture.
The embryoscope has raised pregnancy rates in extracorporeal fertilisation (IVF/ICSI) worldwide. This incubator is equipped with a special microscopic camera that takes seven to eight pictures of each embryo every 20 minutes. With these images it is possible to observe cellular and molecular changes continuously and non-invasively.
In incubators without a special camera, the growth of the oocytes and embryos is checked only once a day. In this way, it is possible to determine whether fertilisation has taken place and whether the embryos will develop in time. However, developmental disorders remain undetected.
The embryoscope, on the other hand, allows a much better identification of the embryo suitable for transfer - in particular using the software KidScore d3 from Vitrolife. This not only results in a higher pregnancy rate than normal incubation, but also reduces the number of treatments required before pregnancy occurs. A publication (Rubio 2014 Fert. Stert.) shows this as well as our own data. We can even show you the pictures of the embryoscope.
Further improved embryo assessment and selection through the use of artificial intelligence
To further increase the chances of pregnancy, we are in the process (01.2010) of establishing an artificial intelligence-based procedure for the assessment and selection of embryos suitable for transfer. This method is based on automatic image recognition to determine the cell division events that occur as the fertilised oocyte matures in the embryoscope. The data thereby obtained is evaluated by a highly complex algorithm that calculates the potential of the embryos individually. As the resulting pregnancy rates are incorporated into the algorithm, it is constantly learning and making better and better recommendations for selecting embryos to be transferred back into the uterine cavity.
In-vitro maturation of oocytes is an option for patients with polycystic ovaries, at risk of hyperstimulation syndrome, or tumour patients. In this procedure, immature oocytes from preantral follicles are punctured without or after short-term hormonal stimulation and then cultured until maturation (metaphase II). This is followed by artificial insemination (IVF/ICSI) with subsequent embryo transfer.
Hope for tumour patients
In-vitro maturation also makes it possible to isolate immature oocytes from frozen ovarian tissue for later maturation in culture. This is particularly important for tumour patients who have had their ovaries removed or in whom chemotherapy and radiation destroy the germ cells.
Not yet a routine application
The method has been in clinical-experimental use for years. Some children have already been born after IVM. However, methodological difficulties remain. This means that at the moment it is not expected that this procedure can be used routinely in the foreseeable future.
In the case of premature onset of menopause - e.g. due to inflammation, ovarian endometriosis or genetic factors - the ovaries can no longer produce oocytes or can only produce oocytes of significantly reduced quantity and/or quality.
Oocyte donation would often be the only alternative here. However, it is not permitted in Germany due to ethical and also legal concerns (Embryo Protection Act).
The attached film shows a fertilised oocyte with normal embryonic development.
Intracytoplasmic sperm injection is an additional method to IVF treatment. In this procedure, a sperm cell is injected directly into the female oocyte. This sperm cell is obtained from the ejaculate - or surgically from the testicle or epididymis. This means that there is no independent fertilisation of oocyte and sperm.
The ICSI method is helpful when sperm motility or quantity is severely limited or fertilisation has failed with conventional IVF treatment. The steps up to oocyte retrieval (link to IVF/treatment steps) are identical for IVF and ICSI.
The oocytes are fixed under a special microscope with a holding pipette. A sperm is then lifted into a thin injection pipette and injected into the oocyte. ICSI (microinjection) mimics the natural process of a sperm penetrating the oocyte. Using this worldwide established method about 50 to 70% of the retrieved oocytes can be fertilised.