For most people conceiving children is simply part of nature. However, there are quite a few women for whom it isn’t. They are unable to conceive, be it due to female or male infertility. Professor Hans-Rudolf Tinneberg, MD, Director Frauenklinik Universitätsklinikum, Giessen, Germany, looks at infertility and Assisted Reproductive Technologies.

Infertility (sterility) or childlessness is the inability of a couple to have a baby when they want. It is a worldwide problem with a prevalence of 10-17 per cent in western countries ranging to an exceptionally low five per cent in China. Infertility is diagnosed when pregnancy does not occur in a couple after two years of unprotected intercourse.

There are several reasons for infertility. It has been shown that regional and economic variation affect infertility. In countries with a relatively low standard of living the number of primary infertile women (women who have never been pregnant) is fairly low, while for secondary infertility (women who have been pregnant before, but can no longer conceive) it is fairly high. It is the opposite in countries with a high standard of living.

Other established reasons for infertility include anatomical abnormalities, such as impaired function of the cervix, intrauterine complications like myomas and factors associated with malfunction of the tubes. Hormonal reasons for infertility include severe cases of ovarian insufficiency, thy-roid gland dysfunction, hyperprolactinemia and luteal insufficiency. Endo-metriosis (distribution of mucosal tissue from the uterine cavity outside the uterus) is believed to be a possible cause for infertility, although this is still under investigation. Environmental factors and psychosomatic are also reasons for infertility. More studies need to conducted to supplement the scant knowledge regarding the role of immunological factors’ influence on infertility.

Male factors are becoming of increasing importance in explaining infertility, such as low sperm count, low motility and decreased number of normally shaped sperm.

Diagnosis

When pregnancy does not occur a very thorough diagnosis has to be performed. It is very important that both partners are examined. As it is easier and less time consuming to assess the fertility of the man, his fertility is examined first. A sperm test (spermiogram) will be conducted after three to five days of sexual abstinence and should be repeated after an interval of minimum six weeks.

Female factors such as polycystic ovarian syndrome (PCOS) and endometriosis, which are particularly prevalent in Arab countries, have to be taken into consideration. The most efficient diagnostic tool is laparoscopy as it allows not only diagnosis but also removal of endometriotic implants.

Therapy

In most cases of male infertility, methods of assisted reproductive technologies (ART) need to be applied such as artificial insemination, in-vitro-fertilisation (IVF) or even intracytoplasmatic sperm injection (ICSI).

In female infertility, blocked tubes can be subjected to microsurgical reconstruction. In severe cases of PCOS new therapeutic regimens such as laparoscopic ovarian drilling or stabilisation of metabolic disorder with oral anti-diabetics can enable the couple to conceive as regular cycles often result.

In cases of endometriosis, a condition where glandular tissue of the uterine cavity is found elsewhere such as in the ovary or in the peritoneum, an anti-hormone therapy or surgical removal of all implants helps ameliorate the chances for achieving a pregnancy. Hormonal problems should of course be balanced out. In frequent cases of luteal phase deficiency, luteal phase support with progesterone or other gestagens can be quite efficient. However, when normalising the menstrual cycle and achieving ovulation as well as stabilising the luteal phase does not result in pregnancy, techniques like IVF need to be considered.

In-vitro-fertilisation

Since the first successful IVF pregnancy in 1978 resulting in the delivery of Louise Brown, many improvements have resulted in IVF becoming a routine method of treating infertility worldwide. Successful IVF pregnancies rates range between 30 per cent and 50 per cent per embryo transfer depending on age of spouse, duration of infertility and capacity of ovaries to produce oocytes (eggs).

The procedure itself requires a hormonal stimulation of the ovaries in order to collect sufficient oocytes for fertilisation. The hormonal stimulation usually involves a pre-treatment with a GnRH-analogue in order to suppress the activity of the pituitary gland. Whilst the pituitary gland is suppressed the ovaries are stimulated using follicle stimulating hormone (FSH) which is currently available as a very clean recombinant product. It stimulates the follicles of the ovaries to mature and produce ovulatory oocytes that will be collected by vaginal sonographically guided aspiration 36 hours after ovulation-induction with human chorionic gonadotrophin (hCG), better known as pregnancy hormone.

Once the oocytes have been collected and dispensed into test tubes the husband’s sperm is added after having been washed and separated from the immotile by a swim up technique (100,000/test tube). In the culture medium environment the sperm fertilise the egg and after 24 hours a pronuclear stage oocyte or two-cell embryo can be detected and 48 hours later four-cell or even eight-cell embryos can be seen just before being transferred into the uterine cavity or alternatively into the tube.

Intracytoplasmatic sperm injection (ICSI)

In case the sperm count is too low or the number of malformed sperm or immotile sperm to high, in-vitro fertilisation as explained above will not occur. Therefore, fertilisation must be instrumentalised. In other words after removing the covering granulosa cells from the oocyte and immobilising the one selected sperm, this sperm is injected into the oocyte through a very fine glass capillary. The oocyte is held via a holding pipette. Pregnancy rates using this method are similar to IVF pregnancy rates. However, a slight increase in the number of malformations has been observed recently.

In some cases of male infertility the ejaculate does not contain any sperm cells. Often, viable sperm can be collected from tissue that has been excised from the testis. In order to prevent multiple testicular operations, the excised tissue is frozen. This allows multiple use of it as only one sperm is required to fertilise an oocyte via ICSI.

Oocyte donation

Unfortunately, in spite of sophisticated techniques five per cent of infertile women are still not considered suitable for the conventional forms of in-vitro fertilisation because they no longer produce any oocytes as their ovaries no longer function or they may risk genetic abnormalities or have oocytes which cannot be matured. In these cases there is no other choice than to use donor oocytes. These may be donated by volunteers or by IVF patients who are prepared to donate superfluous oocytes. These cells can be transferred into the uterus of an infertile woman after fertilisation by her partner’s sperm cells. This technique has raised controversy when applied to woman aged 50 years and more.

Kryopreservation

When more good fertilised oocytes in the pronuclear stage or embryos are available from one IVF cycle than is required for the consecutive embryo transfer, these cells can be stored frozen at -196 CÞ. This process does not damage the oocyte or embryo as it is frozen gradually in a controlled environment to the precise temperature. In the event that the first embryo transfer is not successful, these cells can be used for further embryo transfers thereby achieving a cumulative pregnancy rate per follicular aspiration of more than 70 per cent.

Prof Tinneberg can be contacted by:
Tel: +641-99-45100
Fax: +641-99-45109
Email: hans-rudolf.tinneberg@gyn.med.uni-giessen.de
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