Diagnosis and treatment of infertility
Infertility is an issue which currently impacts around 10-15% of couples in their reproductive years.
The development level of modern reproductive medicine and the correct diagnosis of the cause of infertility allow most couples the opportunity to become biological parents.
Three important rules of treating infertility:
- Begin diagnosis and treatment as soon as possible - unfortunately time works against the couple trying to conceive and one’s biological age does not always match the date on one’s birth certificate.
- Diagnosis and treatment should be conducted at a specialized clinic which offers all available methods of treatment. A fertility treatment centre has a team of doctors of all specializations connected to reproductive medicine who cooperate with each other when treating the couple. The clinics equipment allows for full diagnostic test and all methods of treatment.
- Infertility is a couple’s disease, which is why, no matter the direct cause of the problem, both partners participate in the assessment of reproductive potential and treatment. It has been estimated that 35% of infertility cases are attributed to the female factor, 35% attributed to the male factor, and in 30% of cases the causes of infertility are shared.
Diagnosis and treatment at nOvum begins with arranging the initial consultation over the phone (22 566 80 00) or in person. This first visit, which lasts around an hour, allows the doctor to gather the patient’s medical history. The female patient can be at any point of her cycle after her menstrual bleeding has ceased. During the visit the doctor does a genealogical examination of the patient, performs an ultrasound and reviews any previous test results or treatments.
Diagnosing Female Patients
Diagnosing female infertility is a complex process and can include:
- getting the patient’s medical history,
- gynaecological and ultrasound examinations,
- analytical tests,
- hormone tests,
- monitoring the patient’s cycle,
- examination of the uterus,
- examination of the Fallopian tubes.
- Examination of the uterus
plays a particularly important role in preventing and diagnosing pathologies of the endometrium, including pre-cancerous conditions and cancers. The examination is used to inspect and identify any irregularities to the uterine cavity.
The diagnostic hysteroscope is an optical tube-like instrument which carries light to the uterine cavity through an optical fibre. Equipped with a system of lenses, it enables an accurate examination of the cervix and the uterine cavity. Externally the instrument is connected to a video camera. A diagnostic hysteroscope is introduced to the uterine cavity through the cervix. Carbon dioxide is insufflated to the uterine cavity during the procedure or special distention media are used to enable an exact examination of the uterus. Diagnostic hysteroscopy is performed under general anaesthesia, usually in the latter half of the cycle.
used to treat disorders identified during the diagnostic hysteroscopy. Operational hysteroscopy is performed directly following the diagnostic hysteroscopy or at a later time, if this calls for a special preparation of the patient.
Operational hysteroscopy is similar to diagnostic hysteroscopy, however, the hysteroscope used has a much larger diameter and features an operative channel to introduce scissors, graspers or biopsy instruments. Another version of the operational hysteroscope is the resectoscope which enables the use of the so-called electric loop to eliminate lesions such as fibroids, polyps, septa or adhesions.
If pathological changes to the uterine cavity are suspected, such as uterine malformations, fibroids, adhesions or large polyps, a reference ultrasound examination must be performed. Operational hysteroscopy is performed in the early days of the cycle, but after the menstrual bleeding has stopped. Operational hysteroscopy is performed under general anaesthesia.
is a diagnostic method entailing the injection of a radio-opaque material to the uterus and the Fallopian tubes (if unobstructed) to show the image on X-ray pictures. The examination is performed when instructed by the doctor in order to inspect or precisely determine any specific disorder.
Indications for HSG:
- diagnosis of primary and secondary infertility,
- inspection of developmental issues of the uterus and the Fallopian tubes,
- inspection of potential Fallopian tube obstructions.
HSG is performed during the first 12 days of the menstrual cycle, but always following a complete stop of bleeding and spotting. The procedure is performed under general anaesthesia.The procedure is performed in a gynaecological chair, in an X-ray room and monitored on a TV screen to allow for a dynamic assessment of any potential changes. The radio-opaque contrast is injected after inserting a disposable catheter or Schultz catheter to the cervix while the images of the uterus and the Fallopian tubes are observed on the screen. If unobstructed, the examination continues until the contrast reaches the peritoneal cavity.
At nOvum the examination is performed using an ultra-modern X-ray device, emitting low radiation doses.
the purpose is to observe the woman’s natural menstrual cycle and the changes taking place in her reproductive system: the growth and development of ovarian follicles which potentially contain oocytes, the changes happening in the endometrium as well establishing the best timing for intercourse in order to increase the chances of conception. If the doctor establishes that the follicles do not rupture he or she will suggest an injection of gonadotropins (hCG) in order to induce ovulation. The growth and development of the follicles can be stimulated (induced ovulation) through the administering of clomiphene or gonadotropins. The course of medication is adjusted to the individual needs of the patient.
Endometriosis is a chronic gynaecological condition affecting 5-10% women of reproductive age, leading to a chronic inflammation. It is characterised by the appearance of histopathological areas similar to the endometrium outside the uterus, especially on the peritoneum of the pelvis causing adhesions and Fallopian tube obstruction, on the ovaries leading to cysts and deteriorated oocyte quality, and on the rectovaginal fascia - pain during sexual intercourse.
Sometimes the endometriosis can be found in some fairly atypical locations: on the diaphragm, pleura (chest pains), bladder (bleeding and pain during urination), on the intestines (nausea, bloating, rectal bleeding, irritable bowel syndrome), and even in the brain.
The etiopathogenesis of the disease has still not been fully explained, but the majority of scientists agree that the development of the condition is caused by a hormone - oestrogen.
One of the key roles in the development of endometriosis appears to be played by the immune system which is unable to prevent the implantation of retrograde menstruation. There have also been theories put forward of the disease being a hereditary condition.
The risk factors for endometriosis include an early onset of menstruation, late menopause, shortened menstrual cycles, and obesity. Multiple pregnancies and lactations reduce the risk of endometriosis. Females affected by endometriosis should avoid red meat, dairy products, egg yolks and caffeine, while increasing the amount of fruit and vegetables (cabbage, broccoli, turnips), linseed and fibre in their diets.
Currently a certain way to diagnose endometriosis and its staging (stage I - minimal, stage IV - severe) is an operation (laparoscopy) and histopathological verification. However, for the diagnosis of endometrial cysts in ovaries transvaginal ultrasound is used, with the accuracy of the examination reaching 80-90%. The disease affecting the peritoneum will not be diagnosed using this method.
The marker Ca 125 whose value can be higher for the condition shows low sensitivity.
The procedures for pain syndromes related to endometriosis in patients not treated for infertility include the following:
- Drugs - nonsteroidal anti-inflammatory drugs, progestogens, cyclical or continued administration of combined contraceptive pills, intrauterine devices, therapies using GnRh agonists (risk of bone wastage), or steroids suppressing the synthesis and production of gonadotropins, however rarely used due to their androgenic effects. A new medication was registered in November 2010 to treat endometriosis (dienogest). This is a nortestosterone derivative, without the androgenic effect. Recently, however, aromatase inhibitors have been used more frequently which, by suppressing the action of the aromatase enzyme, result in inhibiting the synthesis of estrogens.
- Operational - procedures include the removal of endometrial cysts and rectovaginal tumours, coagulation of endometrial localisations, and removal of adhesions.
- Combined - drugs and operational.
The treatment of infertile patients diagnosed with endometriosis (approximately 50%) is still a controversial topic.
There is no evidence that the pharmacological treatment of endometriosis in these cases significantly enhances fertility, while delaying other treatment methods, such as insemination or IVF.
The choice of the best therapeutic methodology for infertile patients should provide for a number of factors, such as the patient’s age, time spent treating infertility, time elapsed from the diagnosis of endometriosis and its staging, as well as quality of partner semen.
A good therapeutic option will include the stimulation of ovulation with gonadotropins for intrauterine insemination (especially in the case of stage I and II of the disease), as well as IVF.
Prior to an IVF (long protocol) women in late stages of the disease (stages III and IV) should be first administered GnRh agonists over a period of several months.
A more frequent approach in less advanced stages of endometriosis is to offer laparascopy during which endometrial areas are coagulated and adhesions are removed.
It is recommended that prior to stimulation in expectation of the IVF any endometrial cysts larger than 3 cm are removed. Bear in mind, however, that this procedure may reduce the ovarian reserve.
Note also that endometriosis is not always equivalent to infertility, and a pregnancy is often a great way to treat it.
The polycystic ovary syndrome (PCOS) affects approximately 4-12% women of reproductive age. It is believed to be a hereditary condition with an autosomal dominant trait. Some women develop the PCOS, whereas their mothers and sisters show increased concentrations of androgens. The disorder can be also passed down by men to their daughters. Fathers may be affected by premature hair loss. There have been recorded cases of mothers passing it down with the X chromosome.
The polycystic ovary syndrome can be diagnosed if the patient displays at least two of the so-called Rotterdam criteria.
These include the following:
- oligoovulation and/or anovulation,
- excess androgen levels or skin symptoms of androgenicity,
- specific gynaecologic ultrasound picture.
Females affected by the PCOS also show symptoms of chronic anovulation which is often accompanied by menstrual cycle disorders. The cycles are usually long (exceeding 35 days) and irregular, or there are cases of amenorrhoea (absence of menstrual periods for at least 3 months once pregnancy has been ruled out). The menses, however, are heavy.
Higher levels of androgens may also be related to the total testosterone, free testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione or 17-hydroxyprogesterone (17-OHP). The symptoms of hyperandrogenisation include the following: hirsutism (hair appearing in places typical for males), acne, seborrhoea and, less frequently, hair loss.
The ultrasound image (drawing 1) with a so called ‘string of pearls’ shows numerous (>12 in the field of view) follicles with diameters of 2-9 mm, oriented along the ovarian periphery, under the ovarian cyst. The PCOS ovary volume is usually increased (>10 ml). The central part shows a well-developed stroma. Diagnosis is based on the identification of either or both of the features at the same time during a transvaginal ultrasound.
Prior to diagnosing the following should be ruled out: thyroid disorders, congenital and acquired adrenal hyperplasia, Cushing’s syndrome and sex-hormone producing tumours.
Approximately 50% of the affected patients are overweight. This is often accompanied by high levels of insulin and insulin resistance. This leads to glucose intolerance and may result in developing diabetes.
The pathogenesis of the PCOS is a complex one and is still full of unresolved mysteries. Scientists believe that the condition is caused by metabolic disorders. The key factor responsible for the disease is glucose intolerance which leads to a number of metabolic changes. These in turn cause hormone disorders. Some of the reports focus on the increased production of androgens, active during the foetal phase, as the responsible factor.
Glucose intolerance leads to hyperinsulinaemia and insulin resistance with its receptors also found in the ovaries. Their stimulation results in an increased production of hormones (steroidogenesis) by the ovaries. The important factors for the growth and development of the follicles also include the IGFs (Insulin-like Growth Factors). Their receptors are similar in structure to insulin receptors. It is believed that insulin particles present in elevated concentrations combine with these receptors. The IGF-II receptor is indirectly responsible for the increased production of androgens in the cells of the theca folliculi in response to the activity of the LH (Luteinizing Hormone). Higher concentrations of androgens in the ovaries prevent the growth of the follicles, lead to ovarian follicle and granule cell atresia, whereas the theca folliculi producing androgens lead to the growth of the so-called stroma of the ovary. Excessive androgen production is stimulated by elevated LH concentrations.
Heightened insulin concentration impairs the liver’s production of the sex hormone-binding globulin (SHBG), both androgens and oestrogens, by some 50%. This in turn causes a higher concentration of the free, or active, hormones in the body.
Long-lasting anovulation leading in effect to the capture of numerous follicles in the ovary is typical for polycystic ovaries. It is estimated that 8-25% women of reproductive age show ovarian structures characteristic for the PCOS, but do not display the symptoms of the syndrome. However, such women are believed to be affected by metabolic disorders.
One of the previously adopted diagnostic criteria for the PCOS is the LH/FSH ratio exceeding 2:1. This, however, will not be present in all women affected by the PCOS. The FSH (Follicle-stimulating Hormone) usually remains close to the lower limit or even below, whereas the concentration of the LH is high. The FSH recruits new follicles which cannot mature, however, due to the elevated levels of androgens in the ovaries. The high level of LH is in turn caused by the heightened oestrogen and androgen levels and the hypersensitivity of the pituitary gland. Drawing 2 shows this in a simplified form. The correctly functioning feedback system leads to the development of the "vicious circle" mechanism.
Higher LH levels are associated with the impaired follicular maturation. They have an adverse effect on the process of fertilisation and embryo development.
Hyperinsulinaemia negatively affects the coagulation system, increasing the risk of venous thrombosis, and is by many scientists blamed, in addition to the factors listed above, for the higher risk of miscarriages by females affected by the PCOS.
Insulin resistance is associated with the higher concentrations of the triglycerides and lower levels of the HDL (high-density lipoprotein). In the future this may carry a higher risk of developing not only diabetes, but also ischaemic heart disease and hypertension. Higher levels of oestrogen increase the risk of endometrial cancer and, probably, breast cancer.
The strategy for treating PCOS-affected patients depends on their age and procreation plans. Women who do not wish to get pregnant are offered contraceptive pills which reduce the concentration of androgens and alleviate the associated skin symptoms, while restoring regular menstrual cycles, so important for many women. Another type of therapy involves the administration of progesterone, e.g. between the 16th and 25th day of the cycle. This results in the correct second phase of the cycle, acting as an adjusting factor. It also affects heavy menses and prevents endometrium growth.
The main objective of the therapy for women who are trying to conceive will be to induce ovulation. The first line drug of choice in these cases will be an antioestrogen - clomiphene.
The second line medicines include gonadotropins which are substances developed under laboratory conditions, similar to the FSH and LH hormones produced by the pituitary gland. However, the use of these substances significantly affects the costs of the therapy and increases the risk of a multiple pregnancy.
The dominant follicle growing in the first phase of the cycle does not always contain a regular oocyte. The quality of cells deteriorates with age. It is believed that for a 35-year-old woman some 50% of the follicles are empty (the egg cells degenerate during growth) or contain abnormal oocytes. Stimulating the growth and inducing ovulation for more than one follicle increases the probability of achieving a pregnancy. However, this approach also carries some negative implications. It increases the probability of achieving a multiple pregnancy, and may also result in symptoms of the ovarian hyperstimulation syndrome.
A key factor contributing to the success of the treatment is loss of weight for overweight patients. In many cases this can restore the ovulation and enable a natural pregnancy. It has been proven that the adipose tissue (especially one surrounding the abdomen) produces substances which can have an adverse effect on the embryo implantation process. Obesity can also negatively affect the pregnancy itself. It increases the risk of pregnancy induced hypertension, gestational diabetes, or lead to foetal growth disorders.
A valuable addition to the therapy are medications positively affecting metabolic disorders. Reports indicate also that the use of statins (administered to hypercholesterolemic patients) may have a positive effect on patients demonstrating heightened LH levels. The application of statins along with metformin for a period of 12 weeks positively affected the LH/FSH ratio with those patients, compared to those receiving metformin alone. However, statins are teratogenic drugs and attempts to conceive should be avoided while receiving the medication.
The wedge resection of the ovary, on the other hand, is a thing of the past. The procedure involved the removal of a fragment of the ovary. This led to a reduced concentration of androgens by limiting the number of the stroma cells which produce them. In some women this procedure resulted in restored ovulation. Ovarian drilling is recommended procedure these days. The method involves the drilling of several small holes in the ovarian cyst using coagulation. This works in a way similar to the wedge resection. However, the success rate of ovulation induction using stimulation drugs is currently so high that the procedures described above have been marginalized. Procedures involving ovarian drilling destroy a fragment of the ovarian tissue along with the follicles inside while speeding up the onset of menopause in women.
A woman’s monthly cycle involves the maturation and release of one of the egg cell pre-existing in the ovary. A woman is born with a finite number of cells and the number is never higher than when she is born. The number of cells will become smaller until the day when the supply runs out, the woman enters menopause and ends her reproductive years. This occurs naturally at the age of around 52.
Sometime this happens earlier. Statistically 1 in 1000 women under 30 and 1 in 100 women under 40 experience premature menopause. Before the egg cells are depleted there is a stage we refer to as a limited ovarian reserve. Despite being still of reproductive age according to her birth certificate the woman’s gametes are comparable to those of a much older woman which had consequences for potential motherhood. There are fewer and fewer egg cells and they are of much poorer quality, ovulation becomes infrequent. Even if fertilization is achieved the resulting embryo often has genetic defects and cannot develop further. The causes of the reserves running out sooner have not been entirely identified but scientists name: genetic predisposition, environmental pollution, artificial food additives, smoking and use of stimulants, chemicals, detergents, pesticides, some cosmetics (containing parabens for example); autoimmune diseases also have a negative impact on the reproductive system. The fertility potential of ovaries is assessed based on hormone tests and ultrasound examinations of the ovaries.
Diagnosing Male Patients
Due to the difference in physiology assessing fertility potential, diagnosing infertility and making a decision about the optimal method of treatment is much easier in men than in women. A man who hears the diagnosis: infertile should not lose hope for becoming a biological father. The past 20 years have brought huge advancements in reproductive medicine, which gives countless men the chance to become fathers when in the past they would have had to rely on donor sperm (sperm bank). In modern fertility treatment centres treating male infertility usually ends in success.
The basic test to evaluate male fertility is the seminogram which assesses the concentration, motility, vitality and morphology of sperm and the ejaculate. A doctor’s referral is not required for semen analysis. Prior to the test patients need to abstain from sexual activity for a period of 2 to 7 days (WHO guidelines), and optimally for 3 to 4 days. Patients are also requested to avoid stimulants, stress and excessive physical activity. If prior to the test patients should develop an infection with a high temperature (38-40°C) or be affected by a strong food poisoning, they will be asked to reschedule the appointment.
nOvum offers access to the state-of-the-art equipment to perform semen analysis - the SCA System transforming the microscopic image recorded by a video camera performs a quick and accurate analysis, and generates an objective spermiogram. Over one second the system can analyse over 500 spermatozoa. The motility and concentration are calculated based on a number of images.
Computer assisted semen analysis ensures:
- a quick, accurate and objective analysis of all semen parameters,
- an automatic classification of potential structural defects,
- the ability to generate coloured graphical reports tailored to the needs of individual patients.
At nOvum semen analysis (traditional), computer-assisted semen analysis and semen culture tests are performed by the andrology laboratory on weekdays between 8a.m. and 6.30 p.m. The results can be collected on the same day after 3.30 p.m. but not earlier than 2 hours after the test; the results of tests performed in the afternoon can be collected the next day.
Normal test results
Based on the latest WHO criteria of 2010, the normal semen parameters are as follows:
- ejaculate volume: ≥ 1.5 mL
- pH: 7.0 - 8.0
- sperm count: ≥ 15 million/mL
- sperm count in ejaculate ≥ 39 million
- proportion of sperm with normal motility: ≥ 32% with progressive motility,
- morphology (structure): ≥ 4% of the sperm must have normal morphology
- vitality: > 58% of the sperm
- WBC in sperm: < 1 million/mL
- agglutination test (MAR, IBT): < 50% of the sperm.
Semen tests should be performed at least twice. Even if the test results depart from the standard parameters, it should not be evaluated on its own, without reference to the female test results - as we already stated, infertility is a disease of the couple. The poor quality of partner semen may be mitigated by the enhanced reproductive potential of the female.
Terms referring to ejaculate (according to the WHO criteria of 2010):
- normospermia - normal sperm,
- oligozoospermia - low concentration of sperm in ejaculate ≤ 15 million/mL,
- asthenozoospermia - reduced sperm motility ≤ 40% of the sperm,
- teratozoospermia - abnormal morphology of sperm ≤ 4% of normal sperm
- oligoasthenoteratozoospermia - a combination of the three disorders,
- azoospermia - absence of sperm in ejaculate,
- aspermia - lack of semen.
The test is used to determine whether the semen contains any unwanted bacteria which may lead to infection of the urinary tract or reproductive system. In cases when enough bacteria is present to cause infection an antibiogram (a test to see which group of antibiotics the bacteria are sensitive to) is performed. Usually the results are available after about 4 days.
The drug treatment of male infertility makes use of hormone therapy (testosterone, antiestrogens, prolactin blockers, thyroid hormones, steroids), anti-inflammatory drugs (ketoprofen, diclofenac), vasomotor therapy (pentoxifylline), and dietary supplements (vitamins, microelements).
This often leads to the improvement of semen quality which contributes to the male fertility potential. However, this is a prolonged process taking many months, associated with the long period of producing the male reproductive cells in the testicles (74 days), and any improvements to the quality of the sperm can be seen as late as after 90 days! If the semen quality becomes poor due to bacterial or fungal infections, any improvements can only be achieved following an antibiotic treatment. We must emphasize that pharmacological treatment should be ordered by an experienced andrologist who can judge its relevance correctly. Sometimes we hear about “significant improvements” in sperm quality after patients “independently” treat themselves with over-the-counter medication. However, the patient’s assessment of further test results can be relative. Doubling the sperm count seems like a success but if their number and quality is still below to accepted minimum then chances of conceiving naturally might be low. From the perspective of effective treatment (with the goal being pregnancy) this might be a waste of time.
In the case of urologic diseases surgery is used to improve fertility, including operations of the varicocele, atrophic gonads, the phimosis and the inguinal hernia (guidelines of the European Association of Urology).
Men with azoospermia (no sperm in semen) or aspermia (no ejaculate) can undergo a testicular biopsy (via a needle inserted into the dermis or during an operation) which allows us to assess if spermatozoa are present; if these can be found during a histopathological study of the tissue sample the patient can be referred for treatment through assisted reproductive technology.
When the semen contains no live spermatozoa but hormone tests suggest that the process of spermatogenesis, the creation of spermatozoa, is still present, the spermatozoa can be obtained through the biopsy of the epididymis or testis. The procedure is performed by an andrologist when the patient is under general anaesthesia and feels no pain. The collected tissue is sent to the IVF laboratory where a microscope is used to locate spermatozoa.
nOvum has been performing these procedures since 1996 and since 2012 we have the ability to extract tissue from the testicle under a microscope (M-TESE). It is a much more effective method since we can control what tissue is being extracted during the procedure. If the tissue contains spermatozoa they can be used in the in vitro fertilization process.
When all diagnostic possibilities have been explored and the couple still remains childless we refer to idiopathic infertility, meaning that the available modern methods are not able to reveal its cause. This occurs in around 20% of the couples that seek medical advice. Nevertheless these couples can be treated, conceive and have children. In these cases reproductive medicine specialists focus on solving the problem rather that finding its cause. According to the criteria of European and Polish scientific associations idiopathic infertility lasting over 2 years if the woman is younger that 35 years old and 1 year if the woman is over 35 years old, qualifies the couple for in vitro fertilization. Due to the fact that time works against the woman’s body, with the number of her egg cell and chances of pregnancy dropping with age, postponing the decision of undergoing in vitro fertilization is not advisable.