It is common to take the ability to have children for granted, and to assume that it is possible to achieve parenthood as desired or planned. However, according to the estimation of the World Health Organization, about 50-80 million people (8-10% of the world population) in the world are faced with infertility, which is defined as the inability of a couple to achieve conception or to bring a pregnancy to term after a year or more of regular and unprotected intercourse.
The incidence of infertility in men and women is very similar. It is estimated that in about 30-40% of the cases, infertility is exclusively a female problem, and exclusively a male problem in about 10-30% of the cases. Problems common to both partners are diagnosed in 15-30% of infertile couples. After thorough medical investigations, the causes of the fertility problem remain unexplained in only a minority of infertile couples (5-10%).
There are many causes for infertility but they can be broadly recognized as:
Fertility of a woman decreases with age. The most generally accepted explanation to this is the aging of eggs and the chromosomes inside them. Women are born with all the eggs that they will ever have in their lives. The longer an egg sits around in the ovary, the more likely it is to develop abnormalities in its chromosomes. Therefore, a woman of age 35 would have a lower chance of pregnancy when compared with a woman of age 25. Furthermore, if an egg with abnormal chromosomes is fertilized, there will be greater chances that the resulting pregnancy will end in miscarriage. In fact, chromosomal abnormality is the single most common cause of miscarriage. From many studies, it is known that at least 1/2 of all miscarriages are due to abnormal chromosomes. A young woman (in her 20s), therefore, has only a 12-15% chance of having a miscarriage each time she becomes pregnant. A woman in her 40s has, however, a 50% risk of miscarriage. The aging of eggs also offer an explanation to the increasing chance of giving birth to babies with Down's Syndrome and other chromosomal problems as the age of woman increases.
The diagnosis of "Unexplained Infertility" is used when no cause for the infertility can be found in either partner after in-depth medical investigations. This condition is found in up to 10% of the infertile couples. Couples with unexplained infertility of less than 3-year duration are mostly normal and simply have been unlucky so far. However, after 3 years or more of unexplained infertility, the chances of natural conception are considerably diminished.
Ovulatory disorders are the most common cause of female infertility. Without ovulation, fertilization and pregnancy cannot occur. Ovulatory disorders are characterized by the complete lack of ovulation (anovulation) or by infrequent or irregular ovulation (oligomenorrhea). Infrequent or complete lack of menstruation (amenorrhea) usually indicate ovulatory disorders, but ovulatory disorders can also occur in women who appear to have normal menstrual periods.
When infection and disease attack delicate tubal structures, the tubes may become deformed and cease to function. Trapped in adhesions and scar tissue, they can no longer retrieve the egg and coax it toward the uterus. Also, infection and damage from ectopic pregnancy may strip the vital ciliated lining from the inner walls. When this happens, sperm cannot meet egg, and fertilization cannot occur. If the tubes are obstructed only partially, sperm may be able to meet egg, but the developing embryo can become trapped inside the tube and cause a painful and even life-threatening ectopic pregnancy.
Endometriosis is a very common disorder found in up to 20% of infertile women. It is a condition in which the endometrial tissue, which normally lines the uterus, grows in other areas of the abdominal cavity, on the ovaries, fallopian tube, and often on the bladder and bowel. This implants bleed whenever menstruation occurs, just as they would if they were in the uterus. During menstruation, blood comes out of the cervix and vagina because of the shedding of the uterine lining. With endometriosis the same process takes place inside the abdomen, but in these locations the blood cannot drain out of the body. Thus with every menstrual period there is an inordinate amount of pain, and gradually over the years scarring and distortion of the normal architecture of the tubes and ovaries occur, leading to infertility.
{To diagnose: perform a laparoscopy}
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Abnormalities of the cervix that can cause infertility include anatomical problems, cervical infections and mucus quality. In fact, the mucus lining of the cervix plays an important role in facilitating the progress of sperm through the reproductive tract. During the menstrual cycle, this mucus changes in quantity and quality under the influence of the hormones estrogen and progesterone. Benign tumors or severe scarring of the uterine wall can also contribute to infertility.
Immunological factors also play a role in infertility, but are currently difficult to diagnose and even more difficult to treat. Both partners may be involved; antibodies against sperm can be found in a woman's cervical mucus or a man can even produce antibodies to his own sperm.
In infertile couples, male factors account for 10-30% of infertility problems, while in 15% to 30% of cases both partners have detectable abnormalities. Thus, male infertility plays a significant role in about 50% of infertile couples. The main causes of male infertility can be divided into three categories:
However, in 30% - 40% of cases of male infertility, the origin of the problem remains unexplained. When the reason for the poor quality of sperm cannot be identified, patients are treated with empirical methods. The development of Intracytoplasmic sperm injection (ICSI), a technique introduced in 1992, is beyond doubt the most important recent breakthrough in the treatment of male infertility. Its use in cases of severe male infertility is highly successful.
To determine whether both partners have infertility problems, it is imperative that medical evaluation of both partners be undertaken simultaneously. In addition to physical examination, diagnosis of male infertility includes different laboratory tests such as semen analysis, an essential diagnostic tool to assess the quality of sperm.
Sperm disorders, involving problems in the production and maturation of sperm, are the single most common cause of male infertility.
Although produced in adequate numbers, sperm can be immature, abnormally shaped or unable to move properly, characteristics which will prevent them from fertilizing an oocyte. Normal sperm can also be produced in abnormally low numbers, thus diminishing the chances of fertilization.
Numerous factors can have adverse effects on spermatogenesis. Among these are:
infectious diseases - infectious diseases or inflammatory conditions such as the mumps virus can cause infection of the genital tract or inflammation and atrophy (wasting) of the testes. Approximately 25% of men who contract mumps after puberty become infertile.
endocrine disorders - endocrine or hormonal disorders account for a small share (2-5%) of male infertility cases. Inadequate production of the hormones responsible for testosterone and sperm production - follicle stimulating hormone and luteinizing hormone - are the most common problems.
immunological disorders - some men produce antibodies to their own sperm, resulting in poor sperm motility or agglutination (sperm are linked together by the head or tail and unable to fertilize).
Environmental and lifestyle factors can also affect sperm quality. Exposure to radiation and some cancer treatments may inhibit sperm production either temporarily or permanently.
Anatomical abnormalities obstructing the genital tract can cause infertility as they partially or totally block the flow of seminal fluid. Some of these abnormalities are of congenital origin or the result of a genetic defect, others may have occurred after infection or inflammation of the urogenital tract.
Previous surgery may also be the reason for an obstruction, when scar tissue obstructs the genital tract. Varicocele, the presence of varicose veins in the scrotum (the fibromuscular sac where the testes are located) can contribute to poor sperm quality. Scrotal varicoceles, which are reported in 21% to 41% of infertile males, are usually successfully corrected by surgery.
Male infertility problems can arise from defective delivery of sperm into the female genital tract, a condition that might be caused, among others, by impotence or premature ejaculation.
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The technique of making a baby in a test tube is called in vitro fertilization. In vitro is Latin for 'in glass', and the term signifies that the processes of fertilization occur inside a test tube rather than inside the body.
Although IVF was originally used to treat women with blocked tubes, it has also been used successfully to treat couples with other problems. These include endometriosis, sperm-mucus problems, and 'unexplained' infertility - those couples who have been extensively investigated without any obvious cause for their infertility being discovered.
The main steps in IVF are to
An IVF treatment cycle therefore involves the following stages:
A drug is given in the form of a nasal spray which temporarily switches off the messages going from the brain to the ovaries telling them to produce an egg on a monthly basis. It can be made sure that the drug has worked by taking a blood sample to check the level of oestradiol (one of the oestrogen hormones) and sometimes by performing an ultrasound scan of the ovaries and womb (uterus). In addition down regulation prevents premature release of the egg.
Drugs called gonadotrophins are given in the form of daily injections to stimulate the ovaries to produce several eggs. The eggs grow within small fluid filled spaces called follicles. The response to the drugs is monitored by measuring both the number and size of the follicles and by taking blood samples to measure the levels of oestradiol. When the follicles reach the right size, another drug called hCG is given by a single injection, to ripen the eggs and prepare them for removal.
Eggs cannot be fertilised until they have adaquately matured. The final maturation occurs just several hours prior to the moment of ovulation. To obtain the egg at exactly the right time, the doctor must monitor the changes in the woman's hormone levels. During the first two weeks of the woman's cycle, urinary estrogens are determined every day. When mid-cycle nears and the estrogen level begins to rise, the woman is checked every 3 hours for urinary LH. The key to successful estimation of the time of ovulation is pinpointing the rise in LH.
Ovulation occurs rather predictably 22 hours after the beginning of the rise in LH. The eggs are therefore retrieved 20 hours after the LH surge. The egg is mature at this point and is ready for fertilisation.
To collect the egg, a thin needle is passed through the vaginal wall into the ovaries while they are being scanned on ultrasound. The fluid within each follicle is sucked out and given to the embryologists for them to search for the egg using a microscope.
The procedure is performed using a pain-killer (pethidine) and a sedative (diazepam). This combination of drugs allows doctors to remove the eggs with minimal discomfort for the majority of women.
A few hours after the egg retrieval, the woman's partner is asked to produce a semen sample by masturbation, which is washed and prepared in such a way that a concentrated collection of the most vigorous and active sperm is produced. "Sperm washing" separates seminal fluid from sperm cells. This process removes proteins that could cause allergic reactions, bacteria which may be responsible for infection as well as prostaglandins, a natural constituent of semen, that increases uterine contractions and may expel the sperm sample from the uterus. This washing procedure is also known to enhance the ability of the sperm to penetrate the egg (capacitation).
"Sperm washing" involves repeated dilution of the semen with sterile fluid. The tube containing the liquid is spun at high speeds (centrifugation), separating the sperm cells from the liquid component. The resulting sperm are then removed with a glass tube and returned to a small volume of sterile physiologic buffered solution; they are then ready for insemination.
Sperm and eggs are put together (incubated) overnight in a dish containing a special fluid that provides them with all the right nutrients to allow fertilisation to occur. The next morning the eggs are checked for signs that fertilisation has indeed occurred and on the following day, if embryos have formed, up to a maximum of three are transferred to the mother's womb (uterus).
Embryos are placed gently inside the womb (uterus) on the second day after egg retrieval when they usually consist of two to six cells. They are passed along a thin tube (catheter) which is inserted through the neck of the womb (cervix) into the cavity of the uterus. Embryo transfer is an out-patient procedure which takes only a few minutes to perform and is quite similar to having a cervical smear taken; therefore, no pain relief is required.
In the fortnight after embryo transfer hormones are given, in the form of injections or pessaries, to encourage the lining (endometrium) of the uterus to grow and to help establish a pregnancy.
The number of embryos transferred depends upon several factors, including the number that are available, their quality, the woman's age and the couple's wishes. If three embryos are transferred there is a risk of a triplet pregnancy, which is associated with numerous complications, the most serious being premature delivery. Some couples may therefore decide to have only two embryos transferred even though three may be available to them.
Good quality embryos that are not transferred can be frozen for transfer at a later date. The technique has been used in IVF for some years and has the great advantage of providing embryos for future use without the need for another egg collection. Some embryos however do not freeze very well and do not implant in the uterus as well as fresh ones. Therefore, the success rate is not as high as with fresh embryo transfers.
Intra-cytoplasmic sperm injection was introduced into clinical treatment for certain types of infertility in 1992. It is a type of IVF treatment in which a single sperm is injected directly into the egg. For 1997-1998, the live birth rate of an ICSI cycle is 22.0% compared to 20.6% for conventional IVF.
ICSI is similar to conventional IVF that gametes are collected from each partner. To achieve fertilization, the egg is first held in place using a glass tube with the aid of powerful microscopes and robotic manipulators capable of microscopic movement. A single sperm is aspirated into another thin glass tube and is then injected directly into an egg. Up to three fertilized eggs may then be transferred back to the womb of the women 2 or 3 days after fertilization.
In conventional IVF, eggs and sperms are mixed in a dish and fertilization takes place naturally. In order to fertilize an egg, a sperm has to burrow its way through the mass of granulosa (supporting) cells which are always attached to the outside of the egg. Then it has to traverse the zona pellucida which is a hard protein shell that surrounds the egg. Finally, a single sperm must fuse with the membrane that makes up the egg and in so doing, enter the egg and release its genetic material (chromosomes).ICSI bypasses the natural processes involved in a sperm penetrating an egg, therefore it is used when there are problems that make it impossible to achieve fertilization naturally or by conventional IVF. It is used in situation where
there is high levels of antibodies in the semen
GIFT was developed in 1984 as a variation of the IVF procedure. The ovulation induction and monitoring procedures for GIFT are basically the same as for conventional IVF. After the surgeon retrieves the eggs, the embryologist draws up small amounts of sperm for each egg, and places eggs and sperm into each fallopian tube. If the sperm fertilize the egg, it happens as it would naturally-inside the fallopian tube rather than in an incubator outside the body, as in IVF. Thus, GIFT requires that patients have at least one healthy fallopian tube.
Except for women with two damaged fallopian tubes, candidates for IVF are also candidates for GIFT, which in some centers has a higher pregnancy rate (25 to 35 percent) than IVF. It is most suitable for couples with unexplained infertility, cervical or male factor problems, mild endometriosis, or luteinized unruptured follicle syndrome. GIFT also seems to offer women over forty a better chance at live birth than IVF.
In terms of deliveries per retrieval, GIFT has a higher success rate than IVF regardless of a woman age. This is true whether or not male factor infertility is present. Additionally, GIFT represents an alternative for patients whose religious beliefs prohibit conception outside the body. This is because fertilization takes place within the fallopian tube.
However, GIFT also has some disadvantages when compared to IVF. At present, GIFT usually requires laparoscopy to transfer the eggs and sperm into the fallopian tubes, making it a more major procedure than an IVF embryo transfer through the vagina and cervix into the uterus. Newer developments have led to successful GIFT procedures by placing gametes in the fallopian tube through a tiny catheter threaded through the cervix and uterus. But this technique is more difficult to perform successfully than direct visualization through a laparoscope. More important, GIFT does not allow for visual confirmation of fertilization because it occurs inside the body.
Another variation of conventional IVF is zygote intrafallopian transfer (ZIFT). As in IVF and GIFT, ZIFT involves ovarian stimulation, monitoring and egg retrieval. Sperm are collected, specially processed and used to fertilize the egg in vitro. If fertilization takes place, those eggs that have been fertilized (thus becoming zygotes) are transferred into the fallopian tubes rather than into the uterus. This is accomplished via laparoscopy. ZIFT procedure may also be referred to as tubal embryo transfer (TET). Its general success rate (in terms of deliveries per retrieval) of 24.4%.
ZIFT requires that the woman have at least one functioning fallopian tube. Therefore, ZIFT is not an option in women with infertility caused by tubal problems. However, like IVF, it is possible to determine whether fertilization has taken place. The obvious advantage of ZIFT is that ZIFT uses zygotes, not an egg and sperm mixture.
Intrauterine insemination (IUI) is a common form of artificial insemination (AI). It involves the introduction of sperm into the uterine cavity at time of ovulation. Its goal is to place as many active, well-formed sperm as close to the ovulated egg as possible, thereby increasing their chances of meeting.
IUI is performed in a series of steps. Firstly, the woman's cycle is, with or without medication, monitored so that her time of ovulation is apparent. Then a sperm sample is obtained from the male partner. The sample has optimally been through a process referred to as "sperm washing" as in IVF to remove seminal fluid and inflammatory cells. The sperms are then deposited via a catheter through the cervix high in the uterine cavity close to the fallopian tubes in numbers far greater than normal.
In general, IUI is helpful to couples seeking conception but have unexplained infertility. It is also used in some cases of male-factor infertility, such as low sperm count or decreased motility, and where couples experience poor ejaculation cervical mucus problems and immunologic infertility.
Since the fallopian tubes of the women must be open to allow natural in-vivo fertilization in the fallopian tube, IUI is not applicable in cases where the woman is suffering from structural infertility, such as that caused by severe tubal or uterine damage/blockage. Also, it does not work for couples suffering from ovulatory dysfunction or severe sperm dysfunction