Treatment of Female Infertility
Today, their is a wide range of medical help that can be offered to infertile couple. In thew past five to ten years, there has been an explosion of new information about infertility and great advances, in fertility treatment. These new therapies include advances in hormonal treatment, a wider acceptance of donor insemination, the development of intrauterine insemination (IUI) and advances in micro surgery and laser surgery. However, the most important advances have been made in assisted reproductive technologies (ART). ART includes in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI). Progress has also been made in understanding the psychosocial impact of infertility and in helping couples to manage their worries and emotions through contact with other infertile couples, support groups and counseling.
Correct diagnosis is acrucial step in determining appropriate therapy, and a variety of procedures can be used, ranging from simple blood tests to more complicated analytical methods. Furthermore, as fertility often has several causes, many factors must be considered. Once the diagnosis is established, treatment can be tailored specifically to the individual needs of the couple.
Total infertility is rear and the inability to conceive is generally the result of some degree of subfertility. 'Infertility' can therefore often be overcome. In some cases, surgical correction may be appropriate; in others referral for hormonal treatment or ART may be required. Even in the most extreme cases, where the woman has a premature menopause or the man has a complete lack of sperm, solutions such as sperm and egg donation can be considered.
However, society seems ambivalent about accepting infertility as a legitimate health problem. In Europe, provision for infertility treatment is often limited by healthcare budgets or subject to marked regional variations in availability and/or accessibility. The use of donor eggs or sperm has created great concern and are still matter of heated debate and the use of some forms of ART, such as cryopreservation, has been questioned. Cryopreservation is accepted in some countries but banned in others. Probably no other medical procedures have been subject to such intense religious, moral and social scrutiny as those of assisted reproduction.
Several options for treatment are offered to patients depending upon the type of infertility diagnosed. The vast majority of female patients are successfully treated with the administration of drugs such as clomiphene citrate, gonadotropins or bromocriptine. Surgery can also be a means to repair damage to the reproductive organs such as those caused by endometriosis and infectious diseases. The main approaches to the treatment of the female infertility are given below.
- Ovulation induction (OI)
- Assisted reproductive technology (ART)
- Intrauterine insemination (IUI)
- Intravaginal insemination In Vitro fertilization (IVF)
- Gamete intrafallopian transfer (GIFT)
Ovulation induction (OI)
The female reproductive cycle is regulated by hormones under the control of the hypothalamus, the pituitary gland and the ovaries. If this basic control system does not work correctly, ovulation will be disturbed or absent. Ovulatory disorders are characterized by anovulation (complete failure to ovulate) or infrequent and/or irregular ovulation.
The WHO has adopted a treatment-oriented classification of anovulating patients:
- Group I patients have hypothalmic-pituitary failure. They are amenorrheic and lack both follicle stimulating hormone (FSH) and luteinizing hormone (LH).
- Group II patients have hypothalmic-pituitary dysfunction and present with a variety of cycle disorders including amenorrhoea, oligomenorrhoea and luteal phase deficiencies. About 97% of anovulatory patient fall into this group, including polycystic ovarian disease (PCOD, a condition commonly characterized by hirsutism, obesity, menstrual abnormalities, infertility and enlarged ovaries; thought to reflect excessive androgen secretion of ovarian origin), which is thought to be the most common cause of ovarian dysfunction.
Ovulation induction (OI) aims to correct hormonal imbalances, allowing where possible, monoovulation to occur. More than 80% of infertile women anatomical disorders are treated successfully with fertility agents that promote the growth and development of ovarian follicles vis stimulation of FSH and LH. Agents most commonly used for ovulationinduction are:
- Clomiphene citrate, acting on the hypothalamus to increase the release of gonadotropin releasing hormone (GnRH), which, in turn, stimulate the pituitary gland to release FSH and LH.
- Gonadotropins (FSH and LH acting directly on the ovary, promoting follicular development and hCG triggering ovulation after follicular stimulation).
In WHO Group I patients, Gonadotropin therapy with both FSH and LH is required for follicular development and ovulation. WHO Group II patients may respond to clomiphene citrate. FSH treatment is normally reserved for those who do not respond to clomiphene.
OI is usually combined with timed intercourse or with artificial insemination (also called intrauterine insemination - IUI) in order to increase the probability of successful fertilization. If conception has not taken place after approximately three to five cycles with clomiphene citrate and a further three to five cycles with Gonadotropin treatment, the patient may be referred for ART. The number for clomiphene citrate/Gonadotropin treatment courses is related to the type of infertility, the result of the investigations and reimbursement schemes practiced in each individual country.
FSH is effective in ovarian stimulation. Human chorionic gonadotropin (hCG) injections are used in conjunction with FSH to provoke egg release (hCG is given to mimic the natural LH surge). A frequent adjunct to FSH therapy is synthetic luteinizing hormone releasing hormone (LHRH) analogues which work by suppressing the ovaries. In their suppressed state, the ovaries are more receptive to FSH therapy and higher quality eggs are produced as a result. This is particularly useful for women with PCOD not responding to FSH alone. Bromocriptine is a useful agent in the treatment of hyperprolactinemia, a condition where there is excess of the hormone prolactin in the blood. This condition results in the suppression of GnRH release contributing to anovulation.
Assisted reproductive technologies (ART)
The term ART is used to describe all the methods of artificially assisted conception and refers to several different methods designed to overcome barriers to natural fertilization. The earlier forms of ART were those designed to assist in cases of male infertility, such as assisted transfer of sperms into the vagina or uterus. Intrauterine insemination (IUI) is still widely used today, however mainly for specific cases. Since the first successful birth after IVF in the UK in 1978, many techniques have been developed and success rates have increased dramatically.
Today, ART is called upon for cases of infertility due to anatomical problems (e.g. blocked fallopian tubes), severe male factors (sperm defects, low sperm counts, male and female antisperm antibodies), widespread endometriosis and unexplained infertility. One of these techniques, In Vitro fertilization (IVF) has now been widely practiced for more than 15 years and is the starting point for most ART treatments. Current ART techniques are summarized and described in detail below.
Intrauterine insemination (IUI)
Intrauterine insemination is one of the earlierest form of ART and involves the assisted transfer of sperm into the uterus by means of a catheter directed through the cervix. IUI was originally designed to assist in cases of male infertility. The premise of IUI is that the sperm can reach and fertilize the egg more easily if placed in the uterine cavity. In the 1960s, physicians attempting to enhance the chances of pregnancy injected fresh, untreated sperm (sperm plus seminal fluid) directly into the uterus at the time of ovulation. It was found that when more than 0.2ml of sperm was injected, a serious shock-like reaction insured, later discovered to be a reaction to the prostaglandins found in seminal fluid. Women are protected against this during sexual intercourse by the cervical mucus. The early result of this practice were dismal. However, after the practice of washing the sperm became more common, pregnancy rates using this method increased. IUI is still widely used today but it is limited to assisting women with deficient cervical mucus, which is either poor in quality or hostile to sperm and to women with mild endometriosis.
Intravaginal insemination (IVI)
Intravaginal insemination, again a practice, which has been used for sometime, is now used for donor sperm procedures, artificial insemination partner (AIP) or artificial insemination donor (AID). IVI offers no benifits over normal sexual intercourse, in the case of AIP, but can be useful to circumvent male impotence.
In Vitro fertilization (IVF)
In Vitro fertilization is the process by which eggs (oocytes) and sperm are mixed together outside the body (i.e. in vitro). Following fertilization, resulting embryos are transfered to the woman's uterus 2-5 days later. The IVF process can be summerized in the following five steps:
- The ovaries are stimulated with FSH, in order to cause ripening of several follicles. This is called controlled ovarian stimulation (COS). Successful COS requires very precise day-by-day adjustment of the normal dose. This can only be achieved with the use of FSH in combination with GnRH analogues, allowing the continuous growth of a large number of follicles whilst preventing a spontaneous LH surge through the suppression the natural secretion of FSH and particularly LH. A premature LH surge can cause early ovulation and jeopardize the success of the treatment cycle.
- When ultrasound monitoring indicates that the follciles are large enough to contain an egg that has matured suffeciently, hCG is injected to induce final follicular maturation.
- The eggs are collected about 36 hours after the hCG injection. Egg collection is usually carried out via the vagina under ultrasound guidence utilizing a long hollow needle, although egg collection by laparoscopy (via the abdominal wall) may occasionally be used.
- The eggs are then fertilized with the sperm and the first cell divisions are monitored. Embryos are transferred into the uterine cavity 2-5 days after in vitro fertilization.
Usually more then one embryo is transferred to increase the chances of a successful pregnancy. To avoid the risk of multiple births, it is generally recommended that a maximum of two embryos be transferred. In november 1999, the American Society of reproductive Medicine (ASRM) released guidelines on the number of embryos to be transferred. Under british and german law, a maximum of three embryos can be placed in the uterus at one time, although there is no similar restrictions governing other countries. With the introduction of cryopreservation, excess embryos can be stored for future cycles thus avoiding the patient having to go through ovarian stimulation and egg collection unnecessarily. Cryopreservation is highly regulated in a number of countries.
The success rate of IVF has remained fairly constant for the last six years at around 15%. The success rate falls dramatically after age 40 when only 5% of women treated with their own eggs can expect a live birth.
Gamete intrafallopian transfer (GIFT)
Gamete intrafallopian transfer follows the same procedures as IVF, except that fertilization ocurs in the body (in vivo). The eggs and sperms are placed directly in the fallopian tube where the fertilization can occur.