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AN OVERVIEW OF IVF & ICSI TREATMENTAN OVERVIEW OF TREATMENT WITH INTRA-UTERINE-INSEMINATION (IUI)
AN UNEQUIVOCAL HCG RESULTFISH AND OVARIAN RESERVETREATMENT WITH FROZEN EMBRYO REPLACEMENT
POLYCISTIC OVARIAN SYNDROME (PSOC) & INFERTLITY
AN OVERVIEW OF IVF & ICSI TREATMENT
In vitro fertilization IVF
The basic principle of IVF treatment includes; stimulation of the ovaries to produce a large quantity of eggs, the fertilizing of the eggs with the sperm in the laboratory and finally, the replacement of embryos (fertilized eggs that started dividing into cells) into the uterine cavity.

To achieve the production of multiple eggs, female hormones containing FSH (Follicle Stimulating Hormone), are administered on a daily basis for between 8 – 14 days depending on the patient’s response. During this time patients will be seen on average four times and to accommodate patients not having to take time off from work the scans are performed early in the mornings. To prevent premature ovulation and the release of the eggs into the abdomen a second hormone is also administered throughout the treatment cycle. Approximately 36 hours before the time that the eggs will be collected a final hormone is administered which will ensure that the eggs become ready for collection.

The egg collection takes place in the procedure room and is done under light sedation. Patients are semi-asleep as a result of intravenous drugs administered at the time; however the level of sleep is light enough and allows for patients to still breathe on their own. The actual procedure takes no more than 20 minutes and involves a needle injection through the vagina into the adjacent ovary and the aspiration of the follicles into tubes. These tubes are then passed to the embryologist who at the time will search for the microscopic small eggs contained inside the fluid. All the follicles that are of a certain minimum size will be drained. Afterwards the patient is taken to the recovery area and allowed to leave for home within a couple of hours. Due to the administered drugs patients are not advised to drive or do potentially dangerous activities for the rest of the day, i.e. cooking on a hot stove, etc.

The same morning of the egg collection the male partner / husband hands in a sperm sample. This is washed and prepared by the embryologist and the eggs are then inseminated with the sperm. For those men who prefer specimen pot can be taken home and the sample produced at home, as long as the sample can be handed in within one hour from the time it is produced. The eggs together with the sperm are then placed in a special incubator where it is kept at a certain temperature. Every day an inspection is done and we would normally expect the following rate of development;

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Day 1
This is also known as the day after the egg collection. At this stage we would like to see that the sperm had entered the eggs and there are signs of normal fertilization.

Day 2
At this stage the single fertilized egg that was seen on day 1 should ideally have started dividing into cells. A fertilized egg that started dividing is no longer referred to as a fertilized egg but instead as an embryo. We would normally expect the embryos to be between 2 – 4 cells at this stage. Should the embryo have divided much faster, or very slow, then it leaves us in doubt as to the potential of this embryo to result in a pregnancy. It doesn’t mean that all of these embryos will result in a negative outcome; however it rather indicates that given the choice we would opt to select an embryo between 2 – 4 cells instead.

Day 3
At this stage the embryos should be between 6 – 8 cells. It is at this stage which we can decide to transfer the embryo(s), or alternatively decide to culture (grow) them on until day-5 (blastycysts) and to then transfer them.

BLASTOCYSTS
In those cases where patients have many embryos of a suitable quality on day 3, we can leave the embryos to development for a further 48 hours in the laboratory. On day 4 the cells start to fuse together, a step in the development also known as ‘compacting’. Because the success rates with blastocysts seems quite encouraging many patients always requests treatment with blastocysts transfer. It is important to remember that not all patients will have enough, or suitable quality embryos on day 3 to allow for further growth until day 5. It is also evident that the better success rate seen with blastocysts is not necessarily because they were grown in vitro for a further 48 hours, but rather because their excellent quality made them destined to result in a pregnancy regardless of the day of transfer.

INTRA-CYTOPLASMIC-SPERM-INJECTION (ICSI)
ICSI (intra-sytoplasmic-sperm-injection) is whereby a single sperm is injected into the centre of an egg. This technique is for treatment of couples with moderate to severe male factor sub fertility. By injecting the sperm into the eggs one overcomes the inability of sperm to enter the eggs themselves. The treatment to the female patient is the same as for IVF, as ICSI is merely an added step performed in the laboratory.

ICSI has been used in many centres over the world since it was pioneered in 1992. There is no increased risk to foetal abnormalities when compared to people conceiving naturally. In many centre’s almost half of all IVF cycles account for ICSI treatment.

EMBRYO TRANSFER
This is done in the morning and patients spend on average no more than an hour at the centre. Patients are awake during the procedure and as the procedure is painless, there is no need for any sedation, etc. a very fine catheter is ‘loaded’ with the embryos, which is then inserted via the vagina through the cervix into the uterine cavity where they are slowly released. Afterwards patients can lie down for 20 minutes and are then ready to leave the centre. Some doctors prefer a full bladder, as this can press the uterus down and others feel there is no need for this. At our centre we do not require patients to have a full bladder at the time.

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AN OVERVIEW OF TREATMENT WITH INTRA-UTERINE-INSEMINATION (IUI)
The treatment is very similar to cycle monitoring with the difference that, instead o having intercourse at home, a sperm sample is prepared in the laboratory and inserted into the uterine cavity.

The man produces a sperm sample which is then handed in to the laboratory where a special washing and preparation is performed on the sample. By doing so the scientists can separate the less active sperm from the better ones and this helps to maximize the overall quality of the sample that will be inserted. This process takes between 60 – 90 minutes and is done before the insemination procedure which is then done later.

The insemination itself is a very delicate yet painless procedure and involves the positioning of a

speculum in the vagina (same as when having a cervical smear done) and inserting a small catheter through the vagina and cervix into the uterine cavity. Patients barely feel this because of the fineness of the catheter. The sperm, which is drawn up in the catheter is then slowly released into the uterine cavity. Patients are asked to lie down for a few minutes after which they can get dressed and continue with a normal day’s activities, i.e. returning to work, etc. it is advisable to again have intercourse that same evening as this could maximize the overall chance.

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After 14 days a pregnancy test is performed. During this time patients will be asked to take progesterone supplementation as this could also increase the chances of success. As with all women trying to conceive it is important to take Folic Acid in tablet form as this can reduce the risk of certain congenital defects. Should the pregnancy test be positive then it is advisable to continue with the progesterone and Folic Acid and a pregnancy scan will be performed after 2 – 3 weeks to determine the viability of the pregnancy.

In the event of a negative pregnancy test then in certain cases, and depending on the stimulation protocol that was used, patients can again try immediately the next month in which case patients must discuss this with the doctor so that arrangements for a scan on either day 2 or day 3 of the menses (period) can be done. Those patients who already had two cycles that were not successful need to instead consider having a follow-up consultation with the doctor to discuss other options of treatment.

Donor sperm

This treatment is available to couples requiring donated sperm. All sperm are screened for genetic and venereal (sexually transmitted) diseases including HIV. Donor sperm itself can be used for all treatment types but most common is for artificial insemination IUI.

LAPAROSCOPY AND TUBAL ASSESMENT
Understandably, if one or both the Fallopian tubes are blocked then the egg cannot be picked up into the tube where it is supposed to meet with the sperm and for normal fertilization to occur. For this reason it is important that all patients should have had a test to confirm the tubes are patent (open) and free of any disease such as endometriosis. The best investigation is a laparoscopy, which is done under general anaesthetic as a day-case procedure. This will allow direct vision with a camera into the abdomen to view the tubes and other structures. At the same time dye is inserted to confirm the status of the tubes. One can understand if patients who already had a laparoscopy in the past might be reluctant to undergo another procedure, however for those patients who had been diagnosed previously as having problems in the pelvis, and if done a long time ago, it might be useful to again repeat this so as to have a more up-to-date assessment of the situation.

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Alternatively an x/ray can be done at the radiology department whereby dye is inserted through the cervix into the uterine cavity and if the tubes are open then the dye will spill into the uterine cavity, confirming the tubes are open. This is called an HSG (hysterosalpingogram). Albeit it is an important and helpful investigation, nevertheless it is only a two-dimensional picture and cannot conclude on the relation of the tubes to the ovaries, etc.

QUALITY OF SPERM
In order to achieve success with IUI the quality of the sperm must meet with minimum criteria. The sperm can in some cases be used if it is of a lesser quality, but only if the quality is still acceptable and not too low. In those cases where the sperm quality is significantly low then treatment with IVF and injecting the sperm into the eggs (ICSI) should be considered, as this will overcome the inability of poor quality sperm being able to fertilize the eggs.

AN UNEQUIVOCAL HCG RESULT
When patients are asked to have pregnancy test, this can either be confirmed by a qualitative analysis which simply states ‘positive’ or ‘negative’, as also found in urine tests, or a quantitative analysis whereby the pregnancy hormone (HCG) found in the body is measured. The latter is always the test requested by fertility specialists and normally the value should be more than 25 to confirm a viable result if done at the correct date. To understand the implications of a level less than 25, or where the level has not increased significantly over time, one must first understand the background of the production of the HCG hormone.

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Not all of the initial cells of an embryo become the foetus and some of the cells will group together and become different components of the pregnancy, i.e. placental tissue, amnion, sac with water,

foetus, etc. When all of the components develop satisfactory then the production of the HCG hormone is adequate, as also reflected in the initial quantitative HCG level. Where some of the components did not develop correctly the cells producing the HCG hormone becomes sensitive to this and as a result less HCG hormone is being produced. This explains why some patients will have an initial HCG level of less than 25. Over time there will also be a decline in the rate at which HCG is being produced. The HCG production will however continue until finally the body realizes that not all of the components have developed correctly and eventually the production of the HCG hormone will seize and begin to drop.

There are however some cases, albeit very few, where the initial HCG level was less than 25 and yet patients gave birth to a healthy baby, which relates to slow development of the pregnancy in the beginning. For this reason every patient with an initial level of less than 25 will be monitored with follow-up HCG levels until finally, either the levels begin to drop or the scan confirms a clinical viable pregnancy. Unfortunately, and for most patients whose initial levels were well below 25, the prognosis is not always good. Apart from progesterone supplementation to assist hormonally, there is nothing else that doctors can do to avoid a disappointing outcome because in most cases the developing embryo was not programmed correctly. Although these remain disappointing and challenging times for patients, nevertheless one should remain hopeful for the future, as at least it is possible for the embryo to develop in utero and maybe next time another embryo could develop successfully.

FISH AND OVARIAN RESERVE
FSH (Follicle Stimulating Hormone) is secreted by a gland in the brain known as the pituitary gland. The hormones acts as messengers on the ovaries and is responsible for the maturation of an egg each month in the menstrual cycle. Shortly after the onset of the menses (period) then FSH level is still at its lowest level and gradually as the days go on the level slowly increases. If the ovary is still quite functional then very little of this FSH is required. On the other hand, if the ovary is becoming less functional then more and more of the FSH is required. That explains why women who are already in the menopause have higher levels of FSH because their ovaries have become completely non-functional. In example; most women in their 20’s would have FSH levels of around 6 and women in their 70’s would have levels well above 60 or even higher.

As fertility specialists we are always interested in the FSH level of the patient and specifically the value reported at the beginning of the menses, either on day 2 or day 3 of bleeding when we would

expect the level to be at its lowest. The interpretation of the level is then as follows: The younger the patient in general the better the chances to conceive. The higher the FSH levels the more difficult it becomes to conceive. For this reason a woman with a relatively high level of FSH will have a better chance to conceive than an older woman, merely because of her favorable age. This also explains why woman with a certain FSH level who is older has a lesser chance of success than a woman much younger with the same FSH level.

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Further conclusions that can be drawn include the following: The higher the FSH level the less number of eggs we can expect in treatment with IVF (in vitro fertilization) and the poorer the quality of the eggs potentially. Fertilization in this group is sometimes also less and the overall quality of the embryos not that good, which results in less women getting pregnant. The opposite of all these points applies to women with low FSH levels.

Although there are certain medicine that will lower the level, it is important to remember that the level is now artificially being lowered due to the medicine and not because the ovary is suddenly better functioning. There is to date unfortunately nothing we can do to improve on the ovary so that it can restore its potential and reserve. This condition is also referred to as premature ovarian failure, although this term actually relates to those women where the ovary has stopped functioning all together.

It is also advised that patients who once had a raised FSH level should have the test repeated to obtain a better interpretation on whether the level next time is the same, lower (which will be more encouraging) or even higher. A better test for the interpretation of the ovarian status is the anti-Mullerian hormone, which give a more accurate reflection of the ovarian status seen over a longer time frame. Another important point is the FSH level and whether to start with fertility treatment during a certain month: If the level is in a particular cycle slightly lower, them potentially more eggs can be recruited but not significantly more and the overall quality of the eggs will remain unchanged.Finally, it is difficult to give a precise estimate of success when looking at various FSH levels for women in a certain age, but in general one could say that ideally the level should be below 8.0. If the level is between 8 and 10 then chances are reduced and, between 10 to 12 the chance to conceive is lessoned with at least a third compared to those women of the same age group with a level below 8. If the level is around 14 or more then in general the success to conceive becomes less than 10%.

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TREATMENT WITH FROZEN EMBRYO REPLACEMENT
Treatment for the replacement of frozen embryos can in many cases be quite rewarding with many babies born as a result. The treatment is also mush ‘easier’ than for so-called fresh IVF treatment, as there is no stimulation of the ovaries and therefore no daily injections are required.

Treatment can be offered in three ways namely:

  1. Non-stimulated, drug free cycle.
  2. Stimulation with hormones (tablets) and no injections.
  3. Stimulation with hormones including ovarian down-regulation.

In most cases we would opt for number ‘B’, which compromises of the following:

  • Patients are seen on either the 2nd or 3rd day of their menses (period) a scan is done to confirm there are no ovarian cysts that could potentially have an adverse effect on the treatment.
  • Should the scan findings be satisfactory then patients are prescribed oestrogen in the form of tablets taken daily. These are continued until the time of the pregnancy test and if the outcome is positive then patients will in fact continue with this regime for several weeks into the pregnancy. The oestrogen is responsible for ‘building up’ and thickening of the lining of the uterine cavity, also called the endometrium.
  • Over the course of the next two weeks are seen for two more scans to confirm adequate development of the endometrium.
  • Once the endometrium appears favorable on the scan, and usually after at least 12 days on oestrogen replacement, progesterone in the form of pessaries (Cyclogest®) or tablets inserted vaginally (Ultrogestan®) are prescribed. Patients will then continue from this point on with both the oestrogen and the progesterone until the pregnancy test and once again, if positive then treatment with both will continue for several weeks into the pregnancy. Patients should under no circumstances stop the medicine unless the treatment was unsuccessful.
  • A few days after the progesterone therapy has begun, and depending also at what stage of the development the embryos had been frozen, a date and time will be given for the transfer procedure, which is done exactly the same as with the transfer of the ‘fresh’ embryos during IVF treatment.

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For treatment with option C the drug leuprorelin acetate (Lucrin®) is administered at the beginning of the treatment and usually around 7 – 14 days before treatment with oestrogen commences. This is applicable in some patients and the decision will depend on the patients underlying circumstances.

Treatment with option A, whereby no medicine is prescribed can be offered to those patients who have absolutely normal, regular menstrual cycles and who are known to ovulate with adequate endometrium development as a result of their own hormones. Some studies have suggested that this option should only be considered for women under a certain age whose oestrogen level are generally still better than older women. Once the developing follicle with an egg is ready to be released, ovulation induction is achieved by administering a single injection. Depending at what cell stage of development the embryos were frozen, a date and time is then given for the replacement of embryos. There should be enough progesterone within the body following ovulation to supplement this part of the treatment for which there is thus no need to add any more progesterone hormones.

POLYCISTIC OVARIAN SYNDROME (PSOC) & INFERTLITY
PCOS is a fairly common condition associated with infertility and accounts for a portion of women seen at any fertility unit. The main problem is that patients have a hormone imbalance and as result their eggs do not always mature during the menstrual cycle. In most cases where eggs do reach some level of maturity the body does not have the ability to release the eggs from the ovary and as a result patients do not ovulate. Because no egg is released, the sperm therefore does not have an egg to fertilize inside the fallopian tube, which is where normal fertilization occurs.

PCO-syndrome patients normally have several associated clinical signs, which classify them as having the syndrome whereas with polycystic type ovaries only the ultrasound scan findings are typical. Albeit there is a distinct difference between having the syndrome and just having the PCO appearance on ultrasound scan, nevertheless the effect and treatment for infertility in both groups are mostly the same.

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With PCO there is normally one or more of the following characteristics:

  • Many (poly) cysts on the ovaries giving it a characteristic appearance on ultrasound scan and often described as a string of pearls surrounding the center (stroma) of the ovaries.
  • Irregular menstrual cycles.
  • Obesity.
  • Hairy distribution (hirsituism) with increased hair on various parts of the body such as the face, chest, groin, etc.
  • Infertility.
  • FSH to LH hormone ration, which is normally 2: 1, is seem with blood tests as a ration of 1: 2 or more.

TREATMENT
Unfortunately there is not a cure for this condition by simply taking a course of treatment and to reverse the cystic appearance of the ovaries. We can however offer treatment by restoring the normal hormone function and this is achieved medically. Alternatively and in exceptional cases we can advise on surgery to offer direct treatment to the cysts on the ovary.

MEDICALLY
The approach is to stimulate the patient from the onset of her menses (period) so that a few eggs can mature and secondly; the administration of a final hormone so that the eggs can then be released from the ovary where they are picked up by the Fallopian tubes and fertilize with sperm.

Offering stimulation can be done by either just giving clomiphene citrate tablets at the beginning of the cycle for 5 days, or by adding FSH injections on certain days. Which protocol to follow will depend on the severity of the patients’ symptoms and following on the response when only clomiphene tablets were given in the first instance? With all PCO patients there is also a risk that patient can easily over respond to the dosage prescribed, with too many eggs developing. This will directly place the patient at an unnecessary risk for a multiple pregnancy and therefore great care has to be taken to avoid too many eggs from developing but yet, ideally a few should develop and mature. The prognosis for treatment is very good and most patients do conceive but it can in some cases require a few attempts and often it is difficult to say exactly how an individual would react to the stimulation protocol from the onset. We have also seen that there is also an underlying sperm problem the eggs do not always fertilize favorable, as seen in the laboratory with patients undergoing IVF (in vitro fertilization) treatment. To overcome poor fertilization patients do better when the sperm is injected into the eggs so that better fertilization can occur, a technique also known as IVF with ICSI (intra-cytoplasmic sperm injection.) Not all patients would require this form of treatment but this option would be recommended for patients who;

  • Fail to respond adequately to stimulation with minimal FSH dosage.
  • Patients who repeatedly over respond and make too many eggs.
  • Patients with an underlying sperm problem.
  • Patients who had completed 2 or more cycles with intra uterine insemination (IUI) and who are still not pregnant.

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SURGICAL TREATMENT

By making small holes into the ovaries, many of the cysts are destroyed and as a result some patients can benefit from having more regular cycles and as a result they can also now ovulate spontaneously. This option should only be reserved for patients with extreme cases of PCOS. Following this procedure patients can then have a window of opportunity whereby they can conceive naturally, or embark on stimulated treatment and this is especially helpful for those who had difficulty in responding to the treatment protocol. Patients are often concerned that their ovaries are being ‘destroyed’ as a result of drilling fine holes, which is not the case when done correctly and for the right patients. The ovaries are often anyway larger than normal and by drilling fine holes very little of the ovary is being affected but just enough to ensure an improvement. There was a time however when this procedure was done quite too often and also on the wrong patients, but nowadays most fertility specialist would only advise on this in exceptional cases.