Therapy options

This application helps to propose an appropriate fertility therapy method and to find the most suitable clinic worldwide based on the price, duration and legislative options of the treatment in various countries.

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During ICSI just one sperm is injected directly into the egg cytoplasm using a micromanipulative apparatus that transforms imperfect hand movements into fine and precise movements of micromanipulation tools.

Intracytoplasmic Sperm Injection (ICSI) is an assisted reproductive technique (ART) initially developed by Dr. Gianpiero D. Palermo in 1993 to treat male infertility. It is most commonly used in conjunction with in vitro fertilization (IVF). Following IVF procedure, the physician places the fertilized egg into the female’s uterus for implantation. Sperm are obtained by the same methods as with IVF: either through masturbation, by using a collection condom, or by surgically removing sperm from a testicle through a small incision (MESA, TESE). The females are treated with fertility medications for approximately two weeks prior to oocyte retrieval to stimulate superovulation, where the ovaries produce multiple oocytes rather than the normal one oocyte. The oocytes are retrieved by either laparoscopy, or more commonly, transvaginal oocyte retrieval. In the latter procedure, the physician inserts a thin needle through the cervix, guided by a sonogram and pierces the vaginal wall and then the ovaries to extract several mature ova. Before the embryologist can inject the sperm into the oocyte, the sperm must be prepared by washing and exposing it to various chemicals to slow the sperm movement and prevent it from sticking to the injection plate. Also, the oocytes are treated with hyaluronidase to single out the oocyte ready for fertilization by the presence of the first polar body. Then, one prepared sperm is injected into an oocyte with a thin needle. Often, embryologists try to fertilize several eggs so they can implant more than one into the uterus and increase the chance of at least one successful pregnancy. This also allows them to save extra embryos, using cryopreservation, in case later IVF rounds are needed.

After the embryologist manually fertilizes the oocytes, they are incubated for sixteen to eighteen hours and develop into a pronucleate eggs (successfully fertilized eggs about to divide into an embryo). The egg then grows for one to five days in the laboratory before the physician places it in the female’s uterus for implantation.

The chance of fertilization increases dramatically with ICSI compared to simply mixing the oocytes and sperm in a Petri dish and waiting for fertilization to occur unaided (classical IVF procedure). Studies have shown that successful fertilizations occur 50% to 80% of the time. Since the introduction of ICSI, intrauterine insemination (IUI) has decreased in popularity by 80%.

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Up to now, different methodologies to select sperm have been described in the hope of selecting a viable sperm without - or with a low level of - DNA damage. In 2005, it was the first group that reported the use of a hyaluronic acid (HA) assay as a method to select a sperm for use with ICSI (Pic.1). HA is a linear polysaccharide present in the extracellular matrix of cumulus oophorus around the oocyte that seems to play an important role in natural human fertilization. The use of this polysaccharide is based on the theory that hyaluronan is a major constituent of the cumulus oophorous matrix and may play a critical role in the selection of mature, functionally competent spermatozoa during in vivo fertilization. The head of a mature sperm holds a hyaluronan-specific ligand receptor that facilitates mature sperm to unite to hyaluronan. Comparatively, immature sperm do not unite. Competent, mature, biochemically active sperm unite to the hyaluronan where they can be selected by the embryologist and used for ICSI procedure.

The principles of this assay are:
1. expression of the protein HspA2, which indicates sperm maturation;
2. cytoplasmic membrane remodeling, which is responsible for the formation of sperm binding sites for the zona pellucida of oocytes and for HA binding sites. 

It was suggested that immature spermatozoa present low HspA2 levels, fail to undergo cytoplasmic membrane remodeling and consequently are unable to bind to HA.
This modus operandi mimics a focal step in the innate fertilization course of action, the binding of mature sperm to the oocyte complex. As a consequence, the opted spermatozoa are indispensable alike as one that would be successful and doing well in the natural reproductive progression. Nevertheless, this advancement does not imitate the genomic integrity of the spermatozoa and its aptitude to deliver the best paternal contribution to the zygote.
It was shown that binding to hyaluronic acid seems to be related to one or more conventional and one or more functional sperm tests, indicating that spermatozoa from patients with abnormal conventional semen parameters have a higher likelihood for multiple functional abnormalities. In addition, freezing and thawing seems not alter the HA-binding properties of the spermatozoa.
Some previous studies on sperm surface markers have demonstrated that HA-bound spermatozoa are mature and devoid of cytoplasmic retention, persistent histones, apoptotic markers and DNA fragmentation. In addition, a normal frequency of chromosomal aneuplodies, normal and normal nucleus morphology criteria have been correlated positively with HA-bound spermatozoa. In contrast to this hypothesis, some researchers found no correlation between the HA-binding assay (PICSI) and a low degree of DNA damage. The HA-bound spermatozoa did not differ from HA-unbound ones as to DNA fragmentation (19.6% versus 21.4%, respectively). Also it was reported no difference in the sperm morphology between HA-bound and HA-unbound spermatozoa. Such controversy may be due to the different HA binding methods used, the PICSI dish, sperm slow medium and also the sperm morphology criteria: normal nucleus morphology and normal spermatozoa morphology. Other important point to emphasize is the possible influence of the sperm preparation on the outcome of HA binding. It is well defined in literature that semen sample preparations improve motility and morphology. Besides, the kind of semen preparation could impact the final sample quality.

See full description of PICSI


MACS  technique eliminates apoptotic sperms and may be indicated prior to ICSI, in order to guarantee that the injected spermatozoa are not damaged at a molecular level. Alternatively it could be combined with PICSI.

The externalization of the phospholipid phosphatidylserine (PS) to the sperm plasma membrane is a characteristic feature of the apoptotic phenomenon that occurs early during the process of sperm cell death. This basic knowledge has prompted investigators to develop a magnetic-based selection system for sperm cells that can separate early apoptotic from non-apoptotic germ cells (MACS).

Human sperm quality is defined by the classical parameters, concentration, motility and morphology, according to standard WHO diagnostic semen analysis. Nevertheless, hidden anomalies affecting spermatozoa membranes and causing apoptosis are present. Such features are not routinely detected in ejaculated spermatozoa but they have been proven to have a negative impact on ART outcome. Indeed, successful assisted reproduction is mainly dependent on the quality of the sperm plasma membrane, requiring normal integrity and function to provide motility, acrosome reaction, and fertilization. Spermatozoa with impaired membrane integrity occur more frequently in infertile men, partly explaining suboptimal results in assisted medical procreation. However, striking modifications of sperm plasma membrane occur physiologically in ejaculated sperm. During capacitation, there is a lipid remodelling of the sperm plasma membrane due to phospholipids translocation that lead to externalization of phosphatidylserine (EPS) and phosphatidylethanolamine, and to an albumin mediated efflux of cholesterol resulting in an increase in membrane fluidity.

Externalization of phosphatidylserine (EPS) on ejaculated mature spermatozoa is either the result of a plasma membrane modification because of capacitation and/or acrosome reaction or the sign of an early apoptotic phenotype. Apoptosis in ejaculated sperm is the result of a spermatogenetic failure, thus an abortive apoptotic process that started before ejaculation. 

Annexin V binding to spermatozoa characterizes modified sperm plasma membrane. MACS Technology uses annexin V-conjugated superparamagnetic microbeads (50 nm) to separate nonapoptotic spermatozoa from those with deteriorated plasma membranes with EPS. The spermatozoa/microbeads suspension is loaded on a separation MS column (specialized columns for MACS techniques) containing iron balls, which is fitted in a miniMACS separator (magnet), attached to a multistand. The fraction with intact membranes that passed through the column is labeled as MACS -negative fraction, depleted in phosphatidylserine (PS), whereas the fraction composed of apoptotic or deteriorated PS-positive membranes spermatozoa is retained in the separation column and labeled as MACS -positive fraction. After the column is removed from the magnetic field, the retained fraction is eluted using annexin V-binding buffer.

The positive fraction (called like this due to the fact that the spermatozoa stay retained in the magnetic columns because of their damaged DNA) will allow us to recover a negative fraction (made up of spermatozoa with unharmed DNA), with optimal sperm characteristics to be able to proceed. In other words, the spermatozoa passing through the magnetic columns without being retained will prove to have an unharmed DNA and, therefore, they will be eligible to be used.

See full description of MACS


Surrogacy describes an alternate means of conception for individuals who are unable to conceive a child naturally. In surrogacy, one woman (surrogate mother) carries a child for another person/s (commissioning person/couple), based on an agreement before conception requiring the child to be handed over to the commissioning person/couple following birth.

Traditional surrogacy is defined as a woman who agrees to carry a pregnancy using her own oocytes but the sperm of another couple and relinquish the child to this couple upon delivery. The surrogate is naturally or artificially inseminated via IUI, IVF or home insemination. With this method, the resulting child is genetically related to intended father and genetically related to the surrogate mother.

Gestational surrogacy, by contrast, involves a couple who undergoes IVF with their genetic gametes and then places the resultant embryo in another woman’s uterus, the gestational carrier, who will carry the pregnancy and relinquish the child to this couple upon delivery. The resulting child is genetically unrelated to the surrogate. There are several sub-types of gestational surrogacy as noted below.

  • Using the intended mother's egg - a surrogate is implanted with an embryo created by IVF, using intended father's sperm and intended mother's eggs.
  • Using an egg donor - a surrogate is implanted with an embryo created by IVF, using intended father's sperm and a donor egg where the donor is not the surrogate. The resulting child is genetically related to intended father and genetically unrelated to the surrogate.
  • Using a sperm donor - a surrogate is implanted with an embryo created by IVF, using intended mother's egg and donor sperm. The resulting child is genetically related to intended mother and genetically unrelated to the surrogate.
  • Using an embryo donor - a donor embryo is implanted in a surrogate; such embryos may be available when others undergoing IVF have embryos left over, which they opt to donate to others. The resulting child is genetically unrelated to the intended parent(s) and genetically unrelated to the surrogate.

Currently, the use of gestational carriers is far more common than that of surrogates.

The process 

A surrogacy contract is a contract no different to any other contract as it essentially relates to the agreement or promise made by both parties: contract law is primarily concerned with agreements that involve one party, or each party, giving an undertaking or promise to the other party. The rights and duties of the surrogate stem from two basic promises that she makes to the commissioning couple. First, she promises to be treated with the commissioning couple's genetic material (partial/full surrogacy) and carry the child to term. The surrogate will also give an assurance that she will attend regular prenatal appointments so as to ensure the health and safety of the foetus.

Secondly, the surrogate will promise to surrender all rights in the child to the commissioning couple. This latter promise may become complicated if the surrogate is married, as the law presumes that a child born to a married woman is the child of the woman and her husband. However, this presumption is rebuttable and thus, the commissioning couple should from the outset, make it a term of the contract that the surrogate and her husband explicitly agree to make no claim to the resulting child; without this statement, the intention of the parties may be undercut. Such a provision would help reduce emotional strain and the probability of litigation, and would avoid harming the child by involving it in custody proceedings.

A surrogacy arrangement based on contractual intention should not be designed to commodify offspring. Surrogacy arrangements do not deal with fungibles and must not encourage a system where children are treated as goods that may be contracted in and out of. While the notion of surrogacy could understandably figure centrally in the arena of family law, when examining the matrix of relationships embraced by surrogacy, one may see that surrogacy also has a basis in contract law. As with all contracts, they are designed to protect the interests of both parties as well as to bring to fruition, the express and implied terms of the contract. This perspective derives from the basic agreement made between the surrogate and the commissioning couple; the surrogate agrees to carry the foetus to term, for the benefit of the commissioning person/s and, the latter agree to re-compensate the surrogate for her time and expense in carrying out said procedure, of which, would not be possible without her agreement.

Surrogacy arrangement

There are 2 types of surrogacy arrangement:

  • Altruistic (non-commercial),
  • Commercial – there is a payment, reward or any material benefit for surrogate.

Legal aspects

If the jurisdiction specifically prohibits surrogacy, however, and finds out about the arrangement, there may be financial and legal consequences for the parties involved. Some jurisdictions specifically prohibit only commercial and not altruistic surrogacy. Even jurisdictions that do not prohibit surrogacy may rule that surrogacy contracts (commercial, altruistic, or both) are void. If the contract is either prohibited or void, then there is no recourse if one party to the agreement has a change of heart: If a surrogate changes her mind and decides to keep the child, the intended mother has no claim to the child even if it is her genetic offspring, and the couple cannot get back any money they may have paid or reimbursed to the surrogate; if the intended parents change their mind and do not want the child after all, the surrogate cannot get any reimbursement for expenses, or any promised payment, and she will be left with legal custody of the child.

Jurisdictions that permit surrogacy sometimes offer a way for the intended mother, especially if she is also the genetic mother, to be recognized as the legal mother without going through the process of abandonment and adoption.

Often this is via a birth order in which a court rules on the legal parentage of a child. These orders usually require the consent of all parties involved, sometimes including even the husband of a married gestational surrogate. Most jurisdictions provide for only a post-birth order, often out of an unwillingness to force the surrogate mother to give up parental rights if she changes her mind after the birth.

A few jurisdictions do provide for pre-birth orders, generally in only those cases when the surrogate mother is not genetically related to the expected child. Some jurisdictions impose other requirements in order to issue birth orders, for example, that the intended parents be heterosexual and married to one another. Jurisdictions that provide for pre-birth orders are also more likely to provide for some kind of enforcement of surrogacy contracts.

Additionally, the rights of the surrogate or gestational carrier to not relinquish the infant following deliver are not well described.

Parentage order

A parentage order is a court order that transfers parentage from the birth parent/s to the intended parent/s - as part of the surrogacy arrangement. This means the birth mother and her partner (if she has one) no longer have a legal parental relationship with the child and the intended parents become the child’s legal parents. A prebirth form of parentage order could be used.

Surrogacy laws by state

Surrogacy is completely prohibited in Finland, France, China, Iceland, Italy, Japan, Pakistan, Saudi Arabia, Serbia, Spain and Switzerland. 

Countries where a commercial surrogacy is legal and a woman could be paid to carry another's child through IVF and embryo transfer included Georgia, Russia, Thailand, Ukraine and a few US states.

See full description of Surrogacy

How can Hysterectomy affect fertility

Uterus is the main part of female reproductive system and represents the place in the body, where the embryo and fetus develop after the conception. Without the uterus, the eggs from ovaries cannot be fertilized naturally and woman cannot conceive the baby and be pregnant.

Pic.1: Types of hysterectomy
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