Infertility is defined as the inability to conceive after one year (or 6 months for women over 35 years old) of normal, unprotected and regular sexual intercourse. Infertility is not identical to sterility.
Infertility & Sterility
Sterility is a term that may be used in cases of couples that have absolutely no chance to conceive, even with the use of any medical treatment. On the contrary, the term infertility may be used for each couple in reproductive age which, even if apparently cannot conceive, in fact with the use of appropriate treatment method, finally is able to conceive.
According to the World Health Organisation (WHO) about 12-15% of all couples in reproductive age encounter infertility problems. The probabilities of conception amounts to 20-25% per month for fertile couples, which accumulatively amounts to 70% after one year of regular intercourses or 85% after two years of continuous efforts.
Factors of natural pregnancy
It is known that for a conception to occur several favourable factors and parameters should exist. The necessary factors that can lead to a conception are the followings:
- Release of a mature normal egg,during every menstrual cycle, from the ovary and the passage to the fallopian tube
- Deposition of a normal, from qualitative and quantitative point of view, sperm deep in the vagina
- Advance of the sperm to the female genital canal (cervix, endometrial cavity, fallopian canals, fallopian tubes) under favourable conditions until it meets the egg in the ampulla of the fallopian tube
- Fertilization of the egg by the sperm and implantation of the growing embryo in the friendly endometrium
It is obvious that any disorder during any of the above stages may cause infertility.
Male & Female Infertility
At this point we should highlight that this problem concerns alike both partners. In 40% of the cases woman is the source of the problem, in 40% man is the source of the problem and in the rest 20% both are the source of the problem. The substantial participation of both partners is therefore necessary during any discussion or treatment regarding infertility.
- Ovulatory disorders
- Fallopian tubes damages
- Cervical damages
- Uterine abnormalities
- Sperm disorders
- Ejaculation factors: conditions that may block the transfer of sperm during ejaculation – inability of erection
Causes of infertility concerning both sexes:
- Combination of the above causes
- Insufficient sexual behavior
- Stress, alcohol, use of various substances or medications
- Genetic disorders
- Unknown etiology
When diagnosis is possible, the appropriate treatment is proposed.
The infertility evaluation with a view to diagnose the cause having as result the inability to conceive is a process that concerns both partners. In summary, the basic principles for the evaluation of a infertile couple are the following:
Basic principles for infertility evaluation
|Medical History||To investigate the probable causes of infertility so as evaluation to follow specific directions, frequency of sexual intercourses|
|Clinical Examination||To investigate the possible presence of anatomical abnormalities of the reproductive system or other diseases|
|Biochemical examinations||To investigate the function of the reproductive system, as well as the presence of possible hormonal or other disorders|
|Imaging methods||To investigate the female internal genital organs|
In details, the first step of a diagnostic approach is the medical history of both partners.
Some of the essential information that must be collected by the medical history is for instance diseases in progress or in remission, surgeries, way of life, diet, work-related risks, use of contraceptives, prior pregnancies, miscarriages or curettage, sexually transmitted diseases etc.
For instance, below you will find certain useful information that can be discovered by the medical history and from their evaluation:
|Medical History Data||Data evaluation|
|Questions regarding other diseases, apart from those of the reproductive system||There are possible endocrine diseases (thyroidopathies etc.), systemic diseases or use of anti conception medication|
|Radiation therapy for cancer||Damage of the organs of the reproductive system|
|Taking other pharmaceutical medication||ΠRecent or past hormonal therapy, anti conception medication|
|Alcohol consumption/ smoking||In some cases excessive use may cause fertility problems|
|Family medical history||It may indicate a related predisposition to infertility|
|History of previous treatment against infertility||It determines the success or not of previous treatment methods and moreover it can help with differential diagnosis of the infertile partner|
Clinical examination of both partners with a view to investigate systemic or endocrine diseases may provide substantial information. So, for instance pelvic examination may reveal disorders in position, shape and size of interior genital organs while diagnosis e.g. of varicocele or undescended testicles in men may be the beginning for solving the problem.
It follows clinical examination. General laboratory tests (general blood test, general urine test, biochemical tests of the thyroid etc.) usually precede the biochemical examination with a view to discover possible systemic diseases, e.g. disorders in thyroid’s, adrenals’, pituitary’s activity. For instance, hypothyroidism (reduced activity of the thyroid gland) may result in anovulatory cycles.
After general laboratory tests that may include other tests, it follows a more specialised test of the reproductive system. In particular:
Basal body temperature is used for the investigation of ovulation. In most women, there is an increase of body temperature from 36.5 oC about to 37-37.2 oC, immediately after ovulation. This temperature is actually maintained throughout the second stage of the menstrual cycle. The temperature increase is due to progesterone produced during this stage by the corpus luteum.
The temperature monitoring technique consists of daily measurement, before any physical activity, in rectum, beginning on the first day of the menstruation. Usually the temperature measurement lasts for 1-3 cycles and from its results it is indicated whether a woman has or not ovulation, as well as whether intercourse is effectuated on “fertile” days, that is to say the days around ovulation.
A recent LH test in a kit for urines will confirm the exact day of ovulation and makes easier the detection of ovulation without the every day measurement of temperature.
For the investigation of male causes of infertility initially a sperm test is effectuate with the help of a spermogram. In particular:
A microscopic examination of 2 samples of sperm is effectuated (with intervals of 1-2 months) aiming to the motility test, sperm count, sperm size and shape, as well as other sperm parameters.
A small piece of endometrial tissue is taken 1-3 days before the expected menstrual cycle in order to discover the satisfactory effect of progesterone on this tissue.
It is a diagnostic procedure practically not used.
They are used for the calculation of hormones’ levels and they play significant role in diagnosis of disorders that may cause infertility, especially regarding the hypothalamic – pituitary – ovarian axis.
The commonly used measurements are mentioned in the following table:
|Ultrasound||Non-invasive method. With the use of sound waves it is estimated the size and shape of the reproductive system. Extremely useful for the diagnosis of ovarian disorders and monitoring the ovarian follicles growth|
|Laparoscopy||Through a small abdominal incision in the pelvis, a special device is entered allowing direct inspection of the internal genital organs. Particularly useful in cases of damages of Fallopian tubes or endometriosis. It may be combined with surgeries to restore any damages|
|Hysteroscopy||Inspection of the interior of the uterus|
|Hysterosalpingography||Injection of radio-opaque material in the uterine cavity and radiographic inspection of the uterus and the Fallopian tubes|
With the use of all the above clinical and para-clinical tests, the diagnostic approach of subfertility is largely facilitated. It frequently results the existence of more than one problem (e.g. anovulatory cycles in the woman and reduced sperm motility in the man).
Parameters affecting the treatment
Many parameters affect the fertility without necessary being depended on the use of medicines for the subfertility treatment. The success of a pregnancy in terms of health firstly depends on many factors, such as:
- The reason of the specific infertility problem
- The quality of the embryology laboratory (in relation to the number of available embryos)
- The quality of clinical practices (e.g. egg collection and egg transfer technique)
- Compatibility between embryo – uterus
- The type of pharmaceutical preparations to be used during the treatment (influence of the number of ovarian follicles, collected eggs etc.)
Over the years, the efforts to improve and evolve in the field of pharmacotherapy regarding the preparations with FSH (Follicle Stimulating Hormone) action were focused on the check of specific variables with a view to increase the prospects of achieving pregnancy, such as:
- Elimination of protein contaminants
- Significant increase of the stability of active substance from one lot to another
- Substantial improvement of special activity of the preparation
- Significant improve of the purity of the preparation and finally
- Increase of its safety
There are two key- points of the subfertility treatment for the improvement of the ovarian stimulation and therefore of the likelihood to achieve pregnancy:
- The effective medicines for the accurate control of the ovarian stimulation.
- The possibility of personalisation of the treatment, so as to meet the special needs of every patient.
This last point actually is what made the difference during about the last twenty year and on this basis it is considered that even greater achievements will be succeeded in the field of subfertility. Until the early 80s hormones used as medication for the subfertility treatment were found in the urine of women in menopause. Thousand of couples successful used hormones that were exported in this method.
At the early ‘80s it was discovered that it was possible the preparation of hormones through an innovative process regarding genetically recombinant DNA. This discovery, known as Recombinant DNA Technology or Biotechnology acted as a catalyst in focusing on new ways of production of pharmaceutical preparation required for subfertility treatment, thus providing improved effectiveness and efficiency of the active substance with greater uniformity of the active substance between various lots, easier processing and purification and greater safety.
The female infertility treatment is broadly divided in three stages, corresponding to three consecutive steps. In several cases the first step may be successful so the others may be unnecessary. The said steps are as follows:
- First Step: Treatment with the aid of Clomiphene Citrate
- Second Step: Treatment with the aid of Gonadotropins for ovulation induction
- Third Step: treatment with the aid of Gonadotropins and application of ART (Assisted Reproduction Techniques)
Hormones controlled by the hypothalamus, the pituitary and the ovaries regulate female reproductive cycle. If this axis does not function properly, the ovulation is disrupted or not effectuated. Ovulation disorders are characterised by anovulation (complete absence of ovulation) or rare/ irregular ovulation.
The World Health Organisation (WHO) has adopted a classification of anovulatory women on the basis of the approach
· Women of Group Ι: suffer from serious failure in the axis of hypothalamus – pituitary. They have amenorrhoea and do not produce two essential gonadotropins: i.e. Follicle stimulating hormone (FSH) and luteinizing hormone (LH).
· Women of Group ΙΙ: have a dysfunction in the axis hypothalamus – pituitary and so they suffer from a number of disorders among which: amenorrhoea, oligomenorrhoea, luteal phase deficiency etc. About 97% of anovulatory women belong to this group. Moreover, here belong women suffering from polycystic ovarian disease (PCOD), a disease that is often characterised by hirsutism, obesity, irregular menstrual cycles, subfertility and enlarged ovaries. This disease is considered to reflect excessive androgen secretion from the ovaries which is theoretically the most common reason for ovarian dysfunction.
Ovulation induction aims to restoration of the hormonal balance, allowing, where applicable, the effectuation of single ovulation. To more than 80% of women not having anatomical abnormalities have been administered fertility drugs aiming to the follicles development.
The fertility drugs usually used for ovulation induction are the following:
· Clomiphene citrate, acting in the hypothalamus – pituitary axis, causing the increased release of gonadotropin-releasing hormone (GnRH), which, in turn, stimulates the pituitary release of FSH and LH.
· Gonadotropins (drugs with FSH action, acting directly on ovaries, promoting the growth of follicles).
For the First Group of patients according to WHO, for the development of follicles and ovulation it is required to administer 2 gonadotropins, i.e. FSH and LH. Patients of the Second Group according to WHO is possible to correspond to clomiphene citrate. In case of failure of clomiphene citrate, the treatment is continued with the use of gonadotropin drugs for FSH action.
80% of clinical pregnancies are succeeded after 3 IUI attempts. Further attempts do not entail statistical difference in pregnancies.
FSH administration for ovarian stimulation has been found effective. Then it follows the administration of human chorionic gonadotropin (hCG) with a view to ovulation. In several cases it is necessary to administer simultaneously various, synthetic, agonists or antagonists of gonadotropin-releasing hormone (GnRH) that suppress the pituitary. During the suppression, the treatment may be better scheduled and ovaries are more receptive to exogenous treatment with FSH, having as result the production of eggs of better quality. This is especially useful for women suffering from polycystic ovary syndrome and do not correspond to treatment only with FSH.
Finally, bromocriptine is a substance useful to the treatment of hyperprolactinaemia (abnormally high levels of prolactin in the blood). This disease inhibits the secretion of GnRH and contributes to anovulation.
To women suffering from 3rd – 4th degree of polycystic ovary syndrome is administered metformin.
Treatment of Male Infertility
There is intense scientific and medical interest recently regarding male subfertility. Thus, the range of available treatments for cases of subfertility caused by male aetiology includes:
- Surgical operation
- Assisted Reproductive Technologies (ART)