Treatment

PICSI

Metoda combină probabilitatea crescută de fertilizare a ovulului (oferită de ICSI) cu selectarea unui spermatozoid matur pe baza abilității sale de a se conecta la acidul hialuronic. Afinitatea față de acidul hialuronic oglindește maturitatea spermatozoidului, iar selectarea prin această metodă evită injectarea în ovul a spermatozoizilor imaturi, cu funcționalitate slabă.

Assisted Hatching (AHA)

The word hatching means exit. The human embryo is located inside a protective coating, the so-called glycoprotein membrane, just like a chick in an egg. It has to exit this glycoprotein membrane in order to be fixed on the uterine lining.
The hatching usually takes place during day 5 or 6 of the embryo stage. Unfortunately, the embryo cannot hatch on its own every time, in some cases it needs to be assisted.
This special procedure is called “assisted hatching”, which can be applied based on rigorous professional criteria. Such a hatching is necessary if:
  1. The mother is over 35 years old,
  2. The glycoprotein membrane is measurably thicker than the normal one,
  3. The FSH hormone level is higher than 10
  4. A frozen embryo is being transferred
  5. Embryos have already been transferred twice and the woman did not become pregnant.
  6. From a technical point of view the holes artificially created on the glycoprotein membrane are not dangerous for the embryo.
Assisted hatching can be performed in three different ways. The first is the mechanical method, which consists of performing a cut on the surface of the glycoprotein membrane with a glass knife as thin as a hair. In other cases, a similar cut is performed on the glycoprotein membrane with a laser.
The third method is the enzymatic procedure, when the thinning of the membrane is caused with the grinding effect of a special substance.
The lesion on the glycoprotein membrane heals immediately, thus in a tenth of a second its track cannot be seen, not even with a microscope. Causing the lesion on the glycoprotein membrane is however sufficient to form a weak spot and when the embryo tries to exit, it can successfully break the glycoprotein membrane around this weak spot.
Applying assisted hatching significantly increases the fixing rate and this way the number of the successful IVF treatments.

Hysteroscopy, HyFoSy (Hysterosalpingo-foam sonography)

Hysteroscopy

Hysteroscopy allows the inspection of the uterine cavity using an endoscopic device. The main indications of this procedure performed in the field of infertility include: to identify the causes of infertility, habitual abortion, unexplained uterine bleedings (unclarified by other investigations) and lack of implantation after transferring good quality embryos.
With the use of thismethod various pathological changes can bedetected (such as endometrial polyps, adhesions, congenital malformations, endometrial tumors in early stages, etc.), which are not captured by other procedures (curettage biopsy or ultrasound examination). If cases of pathological changes the procedure also allows harvesting samples for histological examination. The investigation is performed using short general or local anesthesia without requiring hospitalization and the patient can leave the clinic about 2 hours after the procedure. It is best performed between days 7-12 of the menstrual cycle and it is preceded by a thorough preparation.

HyFoSy (Hysterosalpingo-foam sonography)

As an alternative toradiographic examination, which has negative effects on the ovaries in terms of fertility, hysterosalpingo-foam sonography (HyFoSy) is a newer available method to verify tubal patency and to detect abnormalities of the fallopian tubes. In order to carry out this investigation the doctor needs only a powerful ultrasound device and a special foam gel that provides visualization of the anatomical structures of interest. The procedure is simple, quick and well-tolerated; it involves either no general anesthesia or radiation of the ovaries, and therefore this method is less damaging to the woman's body. It is best performed in the period between 7-12 days of the menstrual cycle and is preceded by a thorough preparation.

Treatment with medicine

Drug treatment for infertility

A prerequisite of fertilization is that the pituitary gland, the ovary and the uterine lining to be functional.
Until the mid-twentieth century, due to the lack of appropriate knowledge and training, the treatment of infertility was experimentally performed. For the first time in 1945 animal hormones were used in the first part of the cycle, and under their action appropriate uterine lining was obtained for fixing and fertilization. Due to the rapid development of hormonal examination methods, the explosive development of the ultrasound diagnosis and the worldwide spread of the in vitro fertilization method, the extensive use of drug therapy has gained a large popularity.
The cause of infertility is most often a hormone producing disorder of the ovarian function and is can be effectively treated with drugs or surgery. In these cases, the consequence is the lack of ovulation, behind which lies a disorder in the functioning of the brain-midbrain-pituitary gland-ovary axis, but the problem may involve anomalies of other endocrine organs (such as the thyroid gland, adrenal gland).
As it is known, in 25-30% of the cases behind female infertility lie the anomalies of ovulation, out of which the most important is the polycystic syndrome (PCOS), but also different lifestyle habits, excessive sports and diets, stress, obesity can cause disorders of the menstrual cycle, and, as a consequence, sterility.

Midbrain stimulation

Regarding the action mode of different medications, we can say that these compounds connect to the receptors which detect female hormones (estrogen) in the midbrain (hypothalamus), thus indirectly increasing the activity of the ovary. The active substance of these medicines is clomiphene citrate, which has been the medicine widespread used for the stimulation of the ovarian activity since the beginning of the 1960’s. The advantage of the drug is that it can be used orally, has significantly lower price compared to other medicines used for stimulation and its use doesn’t require an intensive clinical observation. Selecting the patients who respond well to the treatment is a serious task of the specialist doctor; otherwise it’s necessary to consider a low degree of efficiency and a low pregnancy rate. 

Decreasing prolactin level

In many patients an increased prolactin level can be noted, the hormone responsible for lactation. In an important part of the cases it has a functional origin (e.g. increased desire to have children, stress conditions etc.). Before beginning a prolactin lowering therapy the presence of pituitary gland hormone producing tumors must be excluded. In cases with severe pathological prolactin elevations, besides the nipple discharge (leakage of a liquid similar to milk), ovulation does not occur, the menstruation is missing and consequently, infertility develops.

Insufficiency of the corpus luteum

The notion of ovulation disorders is in fact a collective notion, which also includes the functional anomaly of the corpus luteum, produced after the ovulation. In order to eliminate these problems, in the second part of the cycle we can use  preparations containing progesterone, for example after the previously mentioned therapy, or in the case of an unknown origin infertility. Most modern formulas are suitable for being introduced into the vagina, thus bypassing the liver, and they are absorbed without general side effects and directly bind to the uterine lining. Besides a lower blood concentration, we can obtain a higher pregnancy rate and we can reduce the frequency of abortions. 

Hormonal injections

These are medicines which act directly on the ovary: these are gonadotropic hormones which may be used in the form of injections. These are mostly obtained from the urine of menopausal patients, while the most recent medicines, which are still rather expensive, are produced with the use of genetic technology. These so-called recombined preparations have several advantages despite their high costs: their use increase the chance of fertilization even by about 30-35%. Since duration of treatment can be shortened, their cost-effectiveness has shown to be improved.

Side effects

Drug therapies can also have side effects. First of all, overstimulation (the ovarian hyper - stimulation syndrome [OHSS]) and ovarian cysts can develop. The mild forms of overstimulation resolve spontaneously (accompanied by mild hypogastric pain), while average and severe forms can be treated only with appropriate treatment, with or without hospitalization and including effective therapies. Without this treatment, complications may occur, even life threatening events. Another disadvantage of overstimulation is that in 20-40% of cases after drug treatment multiple pregnancies can occur. For this reason it is very important that the controlled ovarian stimulation must be initiated by an experienced specialist, based on the appropriate indications. During therapy repeated ultrasound exams and several hormone measurements might be necessary, as these assessments provide an individualized and more effective treatment.

Intra uterine insemination

What is intrauterine insemination (IUI)?

Sometimes nature needs help to start a pregnancy - and the doctor can do this by placing the sperm directly into the uterus through a fine flexible plastic tube. This procedure is called intrauterine insemination (IUI)or artificial insemination with the sperm of the mail partner and its application can increase the chances of egg fertilization after meeting the sperm.

When is IUI used for treating infertility?

IUI is useful when:
  1. The woman has a cervical mucus problem - for example, it may be scanty or may be hostile to the sperm. With an intrauterine insemination (IUI) the sperm bypass the woman’s cervix and enter the uterine cavity.
  2. The man has antibodies to his own sperm. The "good" sperm which have not been affected by the antibodies are separated in the laboratory and used for IUI.
  3. If the man cannot ejaculate into his partner's vagina. This is usually because of psychological problems such as impotence (inability to get and maintain an erection) and vaginismus (an involuntary spasm of the vaginal muscles that make vaginal penetration impossible); or anatomic problems of the penis, such as uncorrected hypospadias; or if he is paraplegic. 
  4. The man suffers from retrograde ejaculation in which the semen goes backward into the bladder instead of coming out of the penis.
  5. For unexplained infertility, since the technique of IUI increases the chances of the eggs and sperm meeting.
  6. If the husband is away from the wife for longer periods of time (for example, husbands who work on ships or work abroad), his sperm can be frozen and stored in a sperm bank and used to inseminate his wife even in his absence.
The procedure is not recommended in men with low sperm concentration and motility, since cell functionality and viability is low.

How is artificial insemination performed?

There are various methods of doing AI (artificial insemination). The crudest and simplest technique involves simply injecting the entire semen sample into the vagina by a syringe. It can be also performed by the partners in their own bedroom. This is called self-insemination. However, this is in fact a waste of time if used for treating an infertility problem. The only indication would be situations when a male partner would be unable to ejaculate directly into the vagina. Although there are doctors still using this procedure, they do not offer a real advantage or help for the couple.

A refinement of this technique is that of using a spilt ejaculate. The first squirt of semen which gushes forth during ejaculation is richest in sperm. This is because the sperm "surf" on the wave of the seminal fluid which carries them forward to the outside world. The man masturbates into a 2-part container, so that this first part goes into one container, while the rest goesinto the second one. The first bottle is saved and its content is used for artificial insemination. This method is applicable for a small proportion of cases (for example for the uncommon problem of a large volume of semen, which "dilutes" the sperm; or where laboratory facilities for sperm processing are not available).

How is IUI performed?

In this method,sperm cells are removed from the seminal fluid by processing the semen in the laboratory and then they are injected directly into the uterine cavity. It is not advisable to inject the semen direct into the uterus, as the semen contains chemicals (prostaglandins) and pus cells which can cause severe cramping or even tubal infection.

How is the IUI timed?

Timing the IUI is very important - it must be done during the maximum "fertile period" when the egg is in the fallopian tube. Determining the time of ovulation accurately using either vaginal ultrasound or ovulation test kits is crucial. A good clinic should provide this as a 7-day week service, since there is a 1 in 7 chance that ovulation will occur on a Sunday - eggs don't take a holiday! It is important to superovulate the wife at the same time (with chlomid or HMG injections), so that she produces more than one egg. Superovulation increases her fertility potential as well, thus increasing the chances of conception by improving the chances of the eggs and sperm meeting.

The IUI is done either when ovulation is imminent or just right after it’s occurrence. Themale partner masturbates into a clean collector - preferably in the laboratory or clinic itself, and after at least three days of sexual abstinence to get optimal sperm counts. Some men may have considerable difficulty producing a semen sample at the appropriate time, because of the tremendous stress they are under, and the "pressure to perform". For these men, using a previously stored frozen sample can be helpful. Stimulant medication can also be used to help them to get an erection, as can using a vibrator.

The highest quality sperm are separated from the rest of the seminal fluid, by special laboratory processing techniques. This separation takes about 1 to 2 hours. The actual insemination procedure is simple and takes only a few minutes to perform. It is painless, though it can be uncomfortable. The wife lies on an examining table, and a speculum is inserted into the vagina. The doctor places the sperm through a thin plastic tube (catheter) through the cervix into the uterus. There may be a bit of uterine cramping at this time; and also some discomfort for about 12 to 24 hours. Some patients may experience a little vaginal discharge after the procedure, and they are worried that all the sperm are leaking out of the uterus. However, this discharge is just the more abundant cervical mucus specific to the ovulation period and the sperms cannot "fall out" of the uterine cavity.

No special bed rest is required after the IUI. Some doctors may repeat the insemination after 24 hours. We usually encourage our patients to have sexual intercourse on the night of the IUI, and for 2-3 days after this as well, to maximize the chances of the sperm and egg meeting.

How are the sperm processed in the laboratory for IUI?

Semen processing allows the doctor to obtain more concentrated sperm with improved motility and activity in a relatively small volume of fluid. Sperm do not remain alive in the culture medium for very long time unless maintained in the right conditions - hence a prompt insemination after sperm processing is important. This is why masturbation and sperm collecting should be done preferably in the clinic, so that time is not wasted in transporting the sperm after the wash.

Laboratory techniques:

There are differentways of processing the sperm, and all of these require special laboratory expertise.
  1. The simplest method is that of washing the semen with a culture medium (by centrifuging it and collecting the pellet) but this is a poor technique and is not recommended.
  2. The swim-up method uses a layering technique, in which a special culture medium is placed above the semen in a test-tube. The high quality sperm will swim up into the culture medium and after 45 to 60 minutes, this medium (with the motile sperms) is removed and injected into the uterine cavity.
  3. The more sophisticated methods today use a density gradient column. This method allows one to separate the good quality sperm from the immotile sperm, the white blood cells and the seminal plasma, because these are lighter than the motile sperms. It provides the best recovery of motile sperms and is the standard technique in use today, especially for poor quality sperm samples.

Recent advances in the IUI treatment

During the past years, doctors have tried adding various chemicals to the processed sperm to try to improve their motility, so as to increase the chances of their reaching their goal. These chemicals include caffeine andpentoxifylline and they may be helpful in some patients.

During IUI, sperms are injected into the uterine cavity in the hope that they will then swim up from here into the fallopian tubes where they can fertilize the egg. But then, why not inject the sperms direct into the fallopian tubes where the egg is present? Technically this method was difficult to accomplish in the past, because the fallopian tubes are very thin. Today, with specially designed catheters (Jansen-Anderson catheter sets), this can be done in the clinic. Thus, the washed sperm can be injected directly into the tubes under ultrasound guidance, without anesthesia or surgery. This is an intratubal insemination - also known as a SIFT - (sperm intrafallopian transfer). However, pregnancy rates are not superior with this method than with IUI, that is why currently it is rarely performed.

Psychologicalissues

Infertile men may be frustrated and may loss self-confidence because they need a doctor's help to do what a "normal man" should have been able to do by himself. This occurs especially when the compare themselves with other potent men who can solve problems on their own. They also feel guilty about having to subject their wife to the pain and discomfort of insemination. Women may feel anger towards their partners for having the fertility issues. The insemination may also make patients feel that someone has "intruded" into their sex life and this may affect their intimacy.

What is the success rate of IUI treatment?

The success rate of IUI depends on several factors. First of all the cause of the infertility problem is important. For example, men with normal sperm counts who are unable to have intercourse have a much higher chance of success than patients who are undergoing IUI for poor sperm counts. In addition, femaleinfertility factors play an important role. If the female is more than 35, the chance of a successful pregnancy is significantly decreased. Generally, the success rate in one cycle varies between 10 and 15%; and the cumulative conception rate is about 50% after 4 treatment cycles. It is worth mentioning that the chance of natural conception in one month is about 15 to 25 %. However, if IUI is going to work for a couple, it usually becomes successful within 4 treatment cycles. If a pregnancy has not resulted by this time, the chances of IUI working for you are very unreal. In these situations assisted reproduction methods (IVF) should be considered.

What are the risks of IUI treatment?

The major risk of IUI today is the possibility of multiple pregnancy.Since the patient is treated with ovarian simulating treatment, more than one egg may get fertilized, resulting in twins or even triplets or quadruplets. Because the doctor cannot precisely control how many follicles will grow or rupture, the risk of a multiple pregnancy is actually even more after IUI rather than with IVF. If too many follicles grow, the stimulating cycle can be cancelled. Also the treatment cycle can be saved by converting it to IVF method. This can be a cost-effective option, since it allows harvesting a large number of good eggs.
Clinics that provide this type of treatment (artificial insemination) usually can monitor their patients, performing hormonal tests and repeated ultrasound scans. However, there are fertility centers where such services are not available ad this can be very time consuming and frustrating for the patient.

Another major risk of IUI is that many gynecologists perform endless rounds of artificial inseminations in the lack of other alternative methods (in vitro fertilization). This can ultimately generate frustration in infertile couples, they lose confidence in doctors and in the medical services provided.

A common problem of this procedure is that many gynecologists persist in doing IUI even when men have a low sperm count (oligospermia). Despite the fact that the injected sperm is previously processed and more concentrated than the ejaculated semen, the rate of success is relatively low and in these cases an IVF associated with ICSI would be a much better option.

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