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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Assisted reproductive technology

Assisted reproductive technology (ART) is the technology used to achieve pregnancy in procedures such as fertility medication, artificial insemination, in vitro fertilization and surrogacy. It is reproductive technology used primarily for infertility treatments, and is also known as fertility treatment. It mainly belongs to the field of reproductive endocrinology and infertility, and may also include intracytoplasmic sperm injection (ICSI) and cryopreservation. Some forms of ART are also used with regard to fertile couples for genetic reasons (preimplantation genetic diagnosis). ART is also used for couples who are discordant for certain communicable diseases; for example, HIV to reduce the risk of infection when a pregnancy is desired.

If conservative medical treatments fail to achieve a full term pregnancy, the physician may suggest the patient undergo in vitro fertilization (IVF). IVF and ART generally start with stimulating the ovaries to increase egg production. Most fertility medications are agents that stimulate the development of follicles in the ovary. Examples are gonadotropins and gonadotropin releasing hormone. After stimulation, the physician surgically extracts one or more eggs from the ovary, and unites them with sperm in a laboratory setting, with the intent of producing one or more embryos. Fertilization takes place outside the body, and the fertilized egg is reinserted into the woman's reproductive tract, in a procedure called embryo transfer.

Intracytoplasmic sperm injection (ICSI) is beneficial in the case of male factor infertility where sperm counts are very low or failed fertilization occurred with previous IVF attempt(s). The ICSI procedure involves a single sperm carefully injected into the center of an egg using a microneedle. With ICSI, only one sperm per egg is needed. Without ICSI, you need between 50,000 and 100,000. 

Two techniques that enable to some extent the selection of physiologically normal spermatozoa have recently been developed. One of these is termed intracytoplasmic morphology-selected sperm injection (IMSI). Here, spermatozoa are selected for ICSI and analysed digitally prior to the microinjection procedure in order to deselect morphologically abnormal spermatozoa. With this technique, abnormalities not visible in standard ICSI procedures have been observed. IMSI increases the pregnancy rate during ICSI cycles, and some data suggests that the level of pregnancy termination is also decreased. A second technique recently introduced to assisted reproduction is that of sperm selection with hyaluronic acid (HA), e.g. PICSI. In this technique, mature sperm with HA receptors are distinguished from immature and abnormal sperm since these do not express such receptors.

Men who ejaculate no sperm, because of blocked tubes in their testes, or because of a genetic condition that prevents their sperm being released, require some form of surgical sperm retrieval to enable ICSI to take place. Epididymal sperm obtained by microsurgical aspiration (MESA) or percutaneous sperm aspiration (PESA) and testicular sperm obtained by surgical excision (TESE) or percutaneous aspiration (TESA) are used in ICSI treatment. Alternatively, the retrieved sperm can be cryopreserved for use in future sperm injection attempts. If all efforts to extract vital sperm cells fails, then donated ones may be recommended.

Infertile couples may also resort to egg donation or embryo donation when the female partner cannot have genetic children because her own eggs cannot generate a viable pregnancy. Surrogacy via a gestational carrier is also an option when a patient's medical condition prevents a safe pregnancy, when a patient has ovaries but no uterus due to congenital absence or previous surgical removal, and where a patient has no ovaries and is also unable to carry a pregnancy to full term.

Among women with older reproductive age, with history of repetitive abortions or genetic disorders, genetic analysis is highly recommended. The PGS/PGD allows studying the DNA of eggs or embryos to select those that carry certain damaging characteristics. It is useful when there are previous chromosomal or genetic disorders in the family, within the context of in vitro fertilization programs. 

The fertilized eggs (embryos) are cultivated under very stringent conditions and examined every day by the embryologist to evaluate their progress. The embryos are usually cultured for 3 to 5 days, before the best one(s) are selected to be put (transferred) in to the womb. 

Morphological assessment of embryo appearance at the proper, distinct time points during development is a routine procedure in embryo selection. Moreover, time-lapse technology improvements has been evaluated as an aid to identify the embryo(s) with the highest implantation potential that enable to objectively select the embryo(s) for transfer. Time-lapse embryo monitoring allows continuous, non-invasive embryo observation without the need to remove the embryo from optimal culturing conditions. 

The technique of selecting only one embryo to transfer to the woman is called elective-Single Embryo Transfer (e-SET) or, when embryos are at the blastocyst stage, it can also be called elective single blastocyst transfer (eSBT). It significantly lowers the risk of multiple pregnancies, compared with e.g. Double Embryo Transfer (DET) or double blastocyst transfer (2BT).

In a natural cycle the embryo transfer takes place in the luteal phase at a time where the lining is appropriately undeveloped in relation to the status of the present Luteinizing Hormone. In a stimulated or a cycle where a "frozen" embryo is transferred, the recipient woman could be given first estrogen preparations (about 2 weeks), then a combination of oestrogen and progesterone so that the lining becomes receptive for the embryo.

Prior to the implantation, the embryo has to escape from the ZP (Zona pellucida), a process known as hatching at the blastocyst. Some embryo implantation problems in patients with recurrent implantation failure may be explained by the inability of the embryo to hatch out of its zona pellucida. In such cases, zona pellucida can be thinned in one part using the laser technique (LAZT - laser-assisted zona thinning) to improve the pregnancy and implantation rate. Media supporting implantation may also improve implantation process. The environment created for the embryos by the cytokine contained in the medium culture "in vitro" very closely resembles the “in vivo” environment (in natural conditions) and thereby improvements their ability to implant and keep itself in mucous membrane, and grow further.

Approximately 14 days after the embryo transfer the woman should have a quantitative beta hCG (Human chorionic gonadotropin). This is the first measurable indication of embryo implantation.

The rate of success for IVF is correlated with a woman’s age. More than 40 percent of women under 35 succeed in giving birth following IVF, but the rate drops to a little over 10 percent in women over 40.

See full description of Assisted reproductive technology

Egg donation

Egg donation is the process by which a woman donates eggs for purposes of assisted reproduction or biomedical research. For assisted reproduction purposes, egg donation typically involves IVF technology, with the eggs being fertilized in the laboratory; more rarely, unfertilized eggs may be frozen and stored for later use. Egg donation is a third party reproduction as part of ART.

Egg donor may have several reasons for donate her eggs:

  • Unrelated donors to the recipients – they do it for altruistic and/or monetary reasons. The European Union limits any financial compensation for donors to at most $1500. In some countries, most notably Spain and Cyprus, this has limited donors to the poorest segments of society. In US, donors are paid regardless of how many egg she produces. In most countries (excluding the US and the UK), the law requires such type of donors to be anonymous.
  • Egg sharing – the woman decides to provide unused egg from her own IVF for another patient.
  • Designated donors – couple bring their friend or the donor specifically to help them.

Procedure

First step is choosing the egg donor by a recipient from the profiles on or clinic databases (or, in countries where donors are required to remain anonymous, they are chosen by the recipient's doctor based on recipient woman’s desired trait). This is due to the fact that all of the mentioned examinations are expensive and the agencies/clinics must first confirm that a match is possible or guaranteed before investing in the process. 

Each egg donor is first referred to a psychologist who will evaluate if she is mentally prepared to undertake and complete the donation process. These evaluations are necessary to ensure that the donor is fully prepared and capable of completing the donation cycle in safe and success manner. The donor is then required to undergo a thorough medical examination, including a pelvic exam, blood tests to check hormone levels and to test for infectious diseases, Rh factor, blood type, and drugs and an ultrasound to examine her ovaries, uterus and other pelvic organs. A family history of approximately the past three generations is also required, meaning that adoptees are usually not accepted because of the lack of past health knowledge. Genetic testing is also usually done on donors to ensure that they do not carry mutations (e.g., cystic fibrosis) that could harm the resulting children; however, not all clinics automatically perform such testing and thus recipients must clarify with their clinics whether such testing will be done. During the process, which usually takes several months, the donor must abstain from alcohol, sexual intercourse, cigarettes, and drugs, both prescription and non-prescription.

Once the screening is complete and a legal contract signed, the donor will begin the donation cycle, which typically takes between three and six weeks. An egg retrieval procedure comprises both the egg donor's cycle and the recipient's cycle. Birth control pills are administered during the first few weeks of the egg donation process to synchronize the donor's cycle with her recipient's, followed by a series of injections which halt the normal functioning of the donor's ovaries. These injections may be self-administered on a daily basis for a period of one to three weeks. Next, FSH is given to the donor to stimulate egg production and increases the number of mature eggs produced by the ovaries. Throughout the cycle the donor is monitored often by a physician using blood tests and ultrasound exams to determine the donor's reaction to the hormones and the progress of follicle growth.

Once the doctor decides the follicles are mature, the doctor will establish the date and time for the egg retrieval procedure. Approximately 36 hours before retrieval, the donor must administer one last injection of hCG to ensure that her eggs are ready to be harvested. The egg retrieval itself is a minimally invasive surgical procedure lasting 20-30 minutes, performed under sedation (but sometimes without any). A small ultrasound-guided needle is inserted through the vagina to aspirate the follicles in both ovaries, which extracts the eggs. After resting in a recovery room for an hour or two, the donor is released. Most donors resume regular activities by the next day.

Laws by state

The legal status and compensation of egg donation has several models across states with examples:

  • Totally illegal procedure (Italy, Germany, Austria, Costa Rica, Sunni Muslim countries, Bahrain, Egypt, Hong Kong, Lebanon, Lithuania, Maldives, Norway, Oman, Pakistan, Philippines, Qatar, Saudi Arabia, Syria, Tajikistan, Turkey, Yemen),
  • Legal, no compensation, anonymous donor (France),
  • Legal, no compensation, non-anonymous donor (Canada),
  • Legal, possible compensation, anonymous donor (Spain, Czech Republic, South Africa),
  • Legal, possible compensation, non-anonymous donor (the UK),
  • Legal, possible compensation, anonymous or non-anonymous (the US).

See full description of Egg donation

ICSI

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%.

See full description of ICSI

Preimplantation genetic diagnosis

Pre-implantation genetic diagnosis (PGD) allows couples with a family history of monogenic disorders, x-linked diseases and known chromosomal abnormality to avoid the transfer of embryos with these specific genetic disorders. The first preimplantation diagnosis was performed in 1989 for sex selection due to an X-linked disease. Currently, there are an estimated 10,000 children who were born after preimplantational biopsies.

PGD essentially consists of several steps: 

  1. ovarian superstimulation 
  2. aspiration of ovarian follicles
  3. oocyte retrieval 
  4. intracytoplasmic injection of oocytes with processed sperm
  5. in vitro culture of fertilized oocytes
  6. blastomere biopsy on D3 or trophectoderm biopsy on D5
  7. genetic testing
  8. transfer of a genetically normal embryo

If the blastocyst is not transferred to a receptive uterus until the 5th or 6th day, it loses the ability to produce an embryo. To preserve this possibility, it must be vitrified for later transfer.

Indications of PGD

Indications are similar to conventional prenatal diagnosis with regard to:

a) genetic risks with monogenic or chromosomal causes
b) major predisposition to tumors
c) non-genetic risks
d) selection of the best embryos in IVF laboratories

As PGD involves both an IVF or intracytoplasmic sperm injection (ICSI) procedure and a genetic study, it is mandatory to predict the number of unaffected embryos obtainable for transfer prior to realizing the procedure. The number depends on the embryogenic potential of the fertilized oocytes and the implicated risk according to the genetic disorder. The embryogenic potential depends mainly on the woman's age and the absence of factors that facilitate the production of incompetent gametes. Generally, when a woman is younger than 35 years and the male produces good quality sperm, the embryogenic potential is approximately 50%. The embryogenic potential decreases when a woman's age increases or when sperm is of inferior quality. However, the genetic risk depends on the type of disorder (recessive, dominant, sex-linked) or if the disorder is chromosomal. Table 1 shows the estimated number of embryos needed to have the chance to transfer some unaffected embryos, based on the reasoning of PGD.

PGD technology has several primary applications:

1) Single gene disorders

a) Recessive monogenic disorders

Examples of recessive disorders are congenital disorders such as cystic fibrosis, Tay-Sachs, and thalassemia, which involve two mutated chromosomes from each healthy carrier parent. When the disorder is molecularly characterized, the mutation may be analyzed in cells removed from a cleavage embryo or blastocyst. Minisequencing is the method of choice. However, when the mutation is not known, it might be determined by a linkage study.

In cases where the mutation has not been identified in one of the parents, the use of polymorphic markers linked to the gene of interest could help to provide a better diagnosis and allow to have more transferable embryos; otherwise, embryos carrying the known mutation would be considered as affected when they could be healthy carriers. Today, with the availability of SNParrays, the characterization of individual mutations is no longer needed.

b) Dominant monogenic disorders

Examples of autosomal dominant disorders are myotonic dystrophy, fascio-scapular-humeral dystrophy, retinoblastoma, Von Hippel Lindau, MEN I and II, Huntington's disease, osteogenesis imperfecta, and achondroplasia.

When the patient has a "de novo mutation" it is necessary to sequence the entire gene to identify the mutation. Once the mutation has been characterized, this sequence can be targeted in the cells removed from the embryo. In contrast, when there are several affected members in the family, PGD can also be addressed with polymorphic markers linked to the respective gene.

Usually, Huntington's disease develops late in life or when the offspring are of child-bearing age. Many of them do not want to perform the genetic study because they do not want to know their genetic status in advance, but they want to make sure that their children do not have the mutation. Unlike prenatal diagnosis, PGD for Huntington's disease avoids disclosure of the status of the carrier of the mutation.

It is well known that people with certain genetic disorders live in communities, such as mute communities for congenital deafness or persons with achondroplastic dwarfism, and that these couples desire PGD to increase their likelihood of having similarly affected offspring. This is a situation in which it is difficult to satisfy the parents because the medical team cannot help them.

c) Sex linked genetic disorders

X-linked disorders are transmitted by the healthy carrier mothers to their sons, while the affected males transmit the condition to their grandchildren through their healthy carrier daughters but not through their sons. When the mutation is characterized, it is recommended to perform PGD by minisequencing the mutation. Some reprogeneticists carry out embryo sexing to avoid the birth of males, in such cases, but, this is not recommended.
Examples of recessive X-linked diseases are hemophilia, Fragile X, and Duchenne muscular dystrophy.

In contrast, dominant X-linked diseases are transmitted by affected women to 50% of their daughters and sons, but affected males do not transmit it to their sons. Examples of diseases linked dominant X are Rett syndrome, incontinentia pigmenti, pseudohyperparathyroidism, and vitamin D-resistant rachitism.

As an example of Y-linked disorders, there are some AZF region microdeleted in the long arm of the Y-chromosome. In this case, the only option to avoid transmission to the offspring is female sex selection.

2) Chromosome rearrangements - constitutional chromosomal abnormalities are present in up to 0.9% in newborns, and are associated with 50-60% of first trimester miscarriages. Most of these aneuploidies are a result of a meiotic non-disjunction event, but about 1/500 individuals carry a balanced structural rearrangement as reciprocal and Robertsonian translocations. Although most present with normal phenotypes, they often suffer from repeated spontaneous abortions and/or fertility problems, and have an increased risk of delivering children with congenital anomalies and/or intellectual disability. Several studies have shown that PGD improves the pregnancy outcome for translocation carriers, especially in patients with recurrent pregnancy losses.

3) PGD for Human Leukocyte Antigen HLA typing - people affected by malignant conditions, such as leukaemia, lymphoma or some other disorders as beta-thalassaemia, sickle cell anaemia, Fanconi anaemia, Wiscott-Aldrich syndrome, X-linked adrenoleukodystrophy and hypoimmunoglobulin syndromes, may benefit from allogenic haematopoietic stem cell transplantation (allo-HSCT), using an HLA-matched, related donor, most often a sibling child. PGD techniques are helpful in two situations: (a) one child has a non-inherited disease such as leukaemia and the parents want to have PGD with HLA typing alone to allow the newborn to be a donor to the sick child; or (b) one child has a heritable disorder and the parents need PGD in order to avoid another affected child, and, at the same time, HLA typing brings the hope of saving the already affected sibling. For ethical reasons, in some countries, only the latter procedure is deemed acceptable.

4) PGD for Rh blood group typing

PGD can also be indicated in women who are Rh negative and are highly sensitized with antibodies against Rh factor. If Rh genotyping in the male shows that he is heterozygous, it is feasible to perform a PGD to avoid possible erythroblastosis fetalis and intrauterine blood exchange transfusion. PGD has also been used in women sensitized by other blood factors, such as the Kell/Cellentano group.

5) Sex selection

Some of the clinics that offer PGD provide it for sex selection for non-medical reasons. Nearly half of these clinics perform it only for "family balancing", which is where a couple with two or more children of one sex desire a child of the other, but half do not restrict sex selection to family balancing. In India, this practice has been used to select only male embryos although this practice is illegal. Opinions on whether sex selection for non-medical reasons is ethically acceptable differ widely, as exemplified by the fact that the ESHRE Task Force could not formulate a uniform recommendation.

Genetic methods used in PGD

There are different approaches for examination of the genetic constitution in PGD. Currently, most PGD are using biochemical techniques based on polymerase chain reaction (PCR), wherein the disease-linked loci are amplified from blastomeric DNA using targeted primers designed specifically for the mutation of interest. PCR diagnosis from a single cell is used for the diagnosis of single gene defects or triplet repeat disorders. Microarray-based comparative genomic hybridization (aCGH) is a molecular cytogenetic technique which is performed for detection of chromosomal rearrangements (and also for aneuploidy screening in PGS). The principle of aCGH is complex analysis of chromosomal constitution of the cell using fluorescently labeled nucleotides spotted on a microchip. The result is compared with control DNA which is known to have no genetic alterations. Array CGH has proven to be a specific, sensitive, fast and highthroughput technique, but a main disadvantage is its inability to detect structural chromosomal aberrations without copy number changes, i.e. low-level mosaicism, balanced chromosomal translocations, and inversions. The latest microchip-based technology – karyomapping – targets approximately 300,000 of the most informative markers in the genome for efficient genome-wide coverage, meaning that any single gene disorder can be screened for. Karyomapping is a modern, very fast and progressive method, which allows the detection of mutations combined with aneuploidy screening in one test. This new approach enables two-stage genetic selection of embryos, increasing chances for selecting the most suitable embryo for transfer.

Biopsy techniques used for PGD

There are several biopsy techniques for pre-implantation genetic testing used to evaluate the DNA of embryos before day 6 of conception. 

They are the following:

  • Polar-body biopsy (assessing female gametes), in which oocyte genotype can be deduced by analysis of the first and/or second polar body. Oocytes considered genetically "normal" can then be utilised for IVF. As it is performed before fertilisation, polar-body analysis offers the possibility of preconception diagnosis without reduction in cell number of the embryo. One clear disadvantage is the inability to assess paternal genotype. However, as 95% of aneuploidies arise in maternal meiosis, there is little loss in efficiency for aneuploidy testing.
  • Blastomere biopsy (aspiration), assessing the 3-day, six-to eight-cell cleavage embryo, in which the zona pellucida is traversed to extract one or two cells.
  • Trophectoderm biopsy, assessing the 5-to 6-day, 120-cell blastocyst. Because more cells can be removed at this stage, it potentially facilitates more accurate diagnosis. These additional 2–3 days in culture, beyond that required for an eight-cell embryo, allow some time for natural deselection of non-progressing or aneuploid embryos.
  • Blastocentesis, in blastocysts on D5/D6, as a new type of noninvasive embryo biopsy based on the presence of cells and DNA in the blastocoelic cavity.

See full description of Preimplantation genetic diagnosis

Preimplantation genetic screening

In the last 30 years, genetic testing techniques have been developed to identify chromosomally normal embryos in vitro, thereby potentially increasing the proportion of successful cycles with elective single-embryo transfer, and minimizing twin-pregnancy complications and miscarriages. This testing is termed "pre-implantation genetic screening" (PGS), in contrast to pre-implantation genetic diagnosis PGD), in which testing is performed for specific genetic defects. 

Today, PGS technologies have evolved to include screening of all 24 chromosomes (22 pairs of autosomes and the 2 sex chromosomes). Ongoing pregnancy rates of about 60% following single embryo transfer have been described in couples with a maternal age of 38 years whose embryos have undergone PGS. It has not, however, been definitively established that the cumulative delivery rates are better with PGS, although it has been argued that the reduction in miscarriage rates and maternal and neonatal complications due to multiple pregnancies justifies the expense of this technology.

Trends toward delayed childbearing have resulted in an increasing number of women of advanced maternal age seeking to become pregnant and in a consequent increase in demand for assisted reproductive technology, most commonly in-vitro fertilization (IVF). In such women, the proportion of aneuploid embryos can exceed 60%, with a risk of miscarriage of about 40%, potentially resulting in significant emotional and financial hardship for affected couples.

Indications for PGS

Commonly quoted indications for PGS include advanced maternal age, repeated implantation failure, recurrent miscarriage, severe male factor infertility, or subfertility (those who experience unrecognized embryonic losses and who are labelled clinically as infertile). It should be noted that the chances of selecting an euploid embryo mainly depend of the number of embryos produced during the procedure. When it is suspected that the couple has a major chromosomal risk due to advanced maternal age or severe male factors, it is mandatory to inform them of the low chance of achieving a pregnancy with the PGS procedure, unless the couple produces many embryos that provide one or two euploid embryos apt for transfer.

  • Advanced Maternal Age

Women at an advanced age have a greater chance of having aneuploid pregnancies because they have increased rates of producing aneuploid oocytes. Oocytes are always the same age as the woman. However, in males, sperm are produced every 65-75 days. Therefore, it might be said that sperm are not the same age as the male. The prolonged arrest of oocytes at meiotic prophase I mainly contributes to aneuploidy due to the decline in competence of the cytoplasm of the oocyte. The number and distribution of chiasmata during prophase I as the weak centromeric cohesion may be the main factor that predisposes aneuploidy that is inherent to age. In fact, the principal cause of oocyte aneuploidy is the precocious separation of sister chromatids rather than classic non-disjunction. In the male, the expected sperm aneuploidy rate is between 0.5 and 1% because the sperm is not the age of the male, but if the sperm is not ejaculated for prolonged periods, it could have a high rate of DNA fragmentation, which is also responsible for abnormal fertilization. Competent oocytes from young women can repair the DNA fragmentation of the sperm, but the oocytes from older women cannot. Therefore, women of advanced age have higher probabilities of having abnormal pregnancies that might end in miscarriage or in a malformed newborn. Most of these embryos are lost during pre or post implantation stages, while a minority come to term. That is why the possibility of miscarriage also increases with the age of the woman (Tab. 1).

  • Recurrent Pregnancy Loss (RPL)

Usually, RPL is defined as two or more consecutive pregnancies lost before 20 weeks of gestation. Different cytogenetic studies of miscarriages in the first trimester of pregnancy show that aneuploidy rates varied between 50% and 80%. Additionally, it has been documented that couples with RPL produce more aneuploid embryos than those who have not had RPL (Pellicer et al., 1999). According to some authors, PGS does not improve the rate of pregnancy in RPL, but increases the chance of birth at term (Platteau et al., 2005).

  • Recurrent IVF Failure (RIF)

RIF is usually defined as the failure of three or more IVF attempts with good quality embryo transfer. Some authors argue that these couples produce more embryos with aneuploidies. However, there is no evidence that PGS improves the rate of pregnancy or live IVF births.

  • Severe Male Factors

As mentioned above, the rate of aneuploidy in spermatozoa from fertile males with a normal spermiogram is much lower than that observed in oocytes, and aneuploidy also does not increase with age in men. On the other hand, sperm aneuploidies increase with the severity of OAT. These findings put in evidence the importance of the genetic risk assessment before the ICSI procedure to predict the chance of success. Now, with the possibility of PGS/PGD and lower costs, FISH is no longer used to assess sperm.

See full description of Preimplantation genetic screening

Sperm donation

Sperm donation is the donation by a male (known as a sperm donor) of his sperm (known as donor sperm), principally for the purpose of inseminating a female who is not his sexual partner. Sperm donation is a form of third party reproduction including sperm donation, oocyte donation, embryo donation, surrogacy, or adoption. Number of births per donor sample will depend on the actual ART method used, the age and medical condition of the female bearing the child, and the quality of the embryos produced by fertilization. Donor sperm is more commonly used for artificial insemination (IUI or ICI) than for IVF treatments. This is because IVF treatments are usually required only when there is a problem with the female conceiving, or where there is a “male factor problem” involving the female's partner. Donor sperm is also used for IVF in surrogacy arrangements where an embryo may be created in an IVF procedure using donor sperm and this is then implanted in a surrogate. In a case where IVF treatments are employed using donor sperm, surplus embryos may be donated to other women or couples and used in embryo transfer procedures. 

On the other hand, insemination may also be achieved by a donor having sexual intercourse with a female for the sole purpose of initiating conception. This method is known as natural insemination.

The donation
Donor sperm and fertility treatments using donor sperm may be obtained at a sperm bank or fertility clinic. Here, the recipient may select donor sperm on the basis of the donor's characteristics, e.g. looks, personality, academic ability, race, and many other factors. Sperm banks or clinics may be subject to state or professional regulations, including restrictions on donor anonymity and the number of offspring that may be produced, and there may be other legal protections of the rights and responsibilities of both recipient and donor. Some sperm banks, either by choice or regulation, limit the amount of information available to potential recipients; a desire to obtain more information on donors is one reason why recipients may choose to use a known donor and/or private donation.

A sperm donor will usually donate sperm to a sperm bank under a contract, which typically specifies the period during which the donor will be required to produce sperm, which generally ranges from 6–24 months depending on the number of pregnancies which the sperm bank intends to produce from the donor. Donors may or may not be paid for their samples, according to local laws and agreed arrangements. Even in unpaid arrangements, expenses are often reimbursed. Depending on local law and on private arrangements, men may donate anonymously or agree to provide identifying information to their offspring in the future. Private donations facilitated by an agency often use a "directed" donor, when a male directs that his sperm is to be used by a specific person. Non-anonymous donors are also called known donors, open donors or identity disclosure donors.

Donor selection
A sperm donate must generally meet specific requirements regarding age (most often up to 40) and medical history. Potential donors are typically screened for genetic diseases, chromosomal abnormalities and sexually transmitted infections that may be transmitted through sperm. The donor's sperm must also withstand the freezing and thawing process necessary to store and quarantine the sperm. Samples are stored for at least 6 months after which the donor will be re-tested for sexually transmitted infections. This is to ensure no new infections have been acquired or have developed during the period of donation. If the result is negative, the sperm samples can be released from quarantine and used in treatments.

Screening includes:

  • Taking a medical history of the donor, his children, siblings, parents, and grandparents etc. for three to four generations back. This is often done in conjunction with the patient’s family doctor.
  • HIV risk assessment interview, asking about sexual activity and any past drug use.
  • Blood tests and urine tests for infectious diseases, such as: HIV-1/2, HTLV-1/2, Hepatitis B and C, Syphilis, Gonorrhea, Chlamydia, Cytomegalovirus (CMV), not all clinics test for this.
  • Blood and urine tests for blood typing and general health indicators: ABO/Rh typing, CBC, liver panel and urinalysis
  • Complete physical examination including careful examination of the penis, scrotum and testicles.
  • Genetic testing for carrier traits, for example: Cystic Fibrosis, Sickle-cell disease, Thalassemia, other hemoglobin-related blood disorders.
  • General health
  • Semen analysis for: sperm count, morphology, motility, acrosome activity may also be tested

Preparing the samples
A sperm donor is usually advised not to ejaculate for two to three days before providing the sample, to increase sperm count and to maximize the conception rate. A sperm donor produces and collects sperm by masturbation or during sexual intercourse with the use of a collection condom.

Sperm banks and clinics usually "wash" the sperm sample to extract sperm from the rest of the material in the semen. A cryoprotectant semen extender is added if the sperm is to be placed in frozen storage in liquid nitrogen, and the sample is then frozen in a number of vials or straws. One sample will be divided into 1-20 vials or straws depending on the quantity of the ejaculate and whether the sample is washed or unwashed. Following the necessary quarantine period, the samples are thawed and used to inseminate women through artificial insemination or other ART treatments. Unwashed samples are used for ICI treatments, and washed samples are used in IUI and IVF procedures.

Anonymity
Anonymous sperm donation occurs where the child and/or receiving couple will never learn the identity of the donor, and non-anonymous when they will. Non-anonymous sperm donors are, to a substantially higher degree, driven by altruistic motives for their donations.

Even with anonymous donation, some information about the donor may be released to the female/couple at the time of treatment. Limited donor information includes height, weight, eye, skin and hair color. In Sweden, this is all the information a receiver gets. In the US, on the other hand, additional information may be given, such as a comprehensive biography and sound/video samples.

Information made available by a sperm bank will usually include the race, height, weight, blood group, health, and eye color of the donor. Sometimes information about his age, family history and educational achievements will also be given.

Different factors motivate individuals to seek sperm from outside their home state. For example, some jurisdictions do not allow unmarried women to receive donor sperm. Jurisdictional regulatory choices as well as cultural factors that discourage sperm donation have also led to international fertility tourism and sperm markets.

Legal aspects
A sperm donor is generally not intended to be the legal or de jure father of a child produced from his sperm. Depending on the jurisdiction and its laws, he may or may not later be eligible to seek parental rights or be held responsible for parental obligations. Generally, a male who provides sperm as a sperm donor gives up all legal and other rights over the biological children produced from his sperm. However, in private arrangements, some degree of co-parenting may be agreed, although the enforceability of those agreements varies by jurisdiction.

Laws prohibits sperm donation in several countries: Algeria, Bahrain, Costa Rica, Egypt, Hong Kong, Jordan, Lebanon, Lithuania, Libya, Maldives, Oman, Pakistan, Philippines, Qatar, Saudi Arabia, Syria, Tajikistan, Tunisia, Turkey, UnitedArab Emirates, and Yemen. 

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Standard IVF

In vitro fertilization (IVF) is a process by which an egg is fertilised by sperm outside the body: in vitro . The process involves monitoring and stimulating a woman's ovulatory process, removing an ovum or ova (egg or eggs) from the woman's ovaries and letting sperm fertilise them in a liquid in a laboratory. The fertilised egg (zygote) is cultured for 2–6 days in a growth medium and is then implanted in the same or another woman's uterus, with the intention of establishing a successful pregnancy.

IVF techniques can be used in different types of situations. It is a technique of assisted reproductive technology for treatment of infertility. IVF techniques are also employed in gestational surrogacy, in which case the fertilised egg is implanted into a surrogate's uterus, and the resulting child is genetically unrelated to the surrogate. In some situations, donated eggs or sperms may be used. Some countries ban or otherwise regulate the availability of IVF treatment, giving raise to fertility tourism. Restrictions on availability of IVF include to single females, to lesbians and to surrogacy arrangements. Due to the costs of the procedure, IVF is mostly attempted only after less expensive options have failed.

The first successful birth of a "test tube baby", Louise Brown, occurred in 1978. Louise Brown was born as a result of natural cycle IVF where no stimulation was made. Robert G. Edwards, the physiologist who developed the treatment, was awarded the Nobel Prize in Physiology or Medicine in 2010. With egg donation and IVF, women who are past their reproductive years or menopause can still become pregnant. Adriana Iliescu held the record as the oldest woman to give birth using IVF and donated egg, when she gave birth in 2004 at the age of 66, a record passed in 2006.

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TESE

Testicular sperm extraction (TESE) is the process of removing a small portion of tissue from the testicle under local anesthesia and extracting the few viable sperm cells present in that tissue for intracytoplasmic sperm injection (ICSI).

The testicular sperm extraction process is recommended to men who cannot produce sperm by ejaculation due to azoospermia, such as that caused by primary testicular failure, congenital absence of the vas deferens or non-reconstructed vasectomy.

The introduction of the technique of intracytoplasmic sperm injection to achieve fertilization, especially using surgically retrieved testicular or epididymal sperm from men with obstructive or non-obstructive azoospermia, has revolutionized the field of assisted reproduction. Testicular sperm retrieval techniques associated with intracytoplasmic sperm injection have reduced the need for donor sperm and given many azoospermic men the chance to become biological fathers.

The extraction of the testicular parenchyma for sperm search and isolation was first described in 1995. For conventional TESE, a standard open surgical biopsy technique is used to remove the testicular parenchyma without the aid of optical magnification. This procedure is usually carried out without delivering the testis. Briefly, a 2-cm transverse incision is made through the anterior scrotal skin, dartos and tunica vaginalis. A small self-retaining retractor can be used to ensure proper exposure of the tunica albuginea. A 1-cm incision is made in the albuginea, and gentle pressure is applied to the testis to aid the extrusion of the testicular parenchyma. A fragment of approximately 5x5 mm is excised with sharp scissors and placed in sperm culture media. Single or multiple specimens can be extracted from the same incision. Alternatively, individual albuginea incisions can be made in the upper, middle and lower testicular poles in an organized manner for the sampling of different areas. The testicular specimens are sent to the laboratory for processing and immediate microscopic examination. The tunica albuginea is closed with a running, non-absorbable suture.


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How can Sertoli cell-only syndrome affect fertility

The process of sperm formation cannot proceed without germ cells present in the testes. Therefore, males suffering from stage I. SCOS are infertile. On the other hand, the stage II. SCOS patients may still have chance of conceiving a child. Even though the sperm counts are way too low to conceive a child in “old fashion” way, the assisted reproduction techniques (ART) offer a possible solution.

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