Reasons for and diagnosis of infertility
Reasons causing infertility have various aspects and concern both the man and the woman. They are often a combination of many reasons, and around 20% of cases remain unexplained.
Below, we list some of the most frequent causes and common diagnostic steps. Please consider that only a tailor-made diagnosis, which takes into account your characteristics, may give the reasons for your case. Therefore, the following pages give general information that serve to diagnose your case.
REASONS FOR AND DIAGNOSIS OF THE INFERTILE WOMAN
Ovulation disorders, hormone disorders (which can be congenital, acquired or due to age) or disorders of the luteal phase.
Post-coital and hormonal tests are necessary for the diagnosis of ovulation disorders. A classic hormonal profile, on the second to fifth day of the cycle, comprises FSH, LH, progesterone, DHAS, SHGB, ACTH, and also the determination of the inhibin B’s content (on the third to sixth day of the cycle) or that of the anti-müller hormone (AMH). The latter are essential for the assessment of the ovarian reserves and can take place on any day of the cycle.
PCOS patients have higher AMH values. A general guideline for AMH values would eventually be:
Excellent ovarian reserves 28-48 pmol/L 4-7 ng/mL
Sufficient ovarian reserves 15-27 pmol/L 2-3.9 ng/mL
Low ovarian reserves 2-15 pmol/L 0.3-2 ng/mL
Almost exhausted ovarian reserves 0.0-2 pmol/mL 0.0-0.3 ng/mL
High values > 46 pmol/mL > 7 ng/mL
Conversion factor: ng/ml x 7.14 = pmol/l
A luteal deficiency can be estimated by measuring the value of progesterone on the 21st day of the cycle and may be treated medicinally.
Inflamed, obstructed or occluded oviducts
Obstructed or occluded oviducts are responsible for an amazingly great number of infertility cases. Often they arise from inflammation and infections and remain unnoticed and without any symptoms. Alternatively, they are the result of an extrauterine pregnancy or adhesions after previous operations or endometriosis. In the case of occluded oviducts, pregnancy is possible only after an IVF treatment, and even then, in many cases the tubes must be previously removed. It is important to exclude hydrosalpinx of the tubes. This is an accumulation of fluids that have possibly have a bad impact on implantation.
A hysterosalpingogram (HSG) gives information regarding the patency of the oviducts. This involves a radiologic examination, which is performed by injecting a contrast fluid in the uterus. For a healthy result, the fluid must run out, whereas in a pathologic case, the fluid stays “hanged” and causes swelling.
The importance of this examination is recognized in certain countries, and an HSG is an indispensable, required examination before one starts treatment for the wished child, whereas in other countries it is often hard to do it. On many occasions, patients must undergo a laparoscopy themselves, which is a difficult examination to organize. A diagnostic laparoscopy is naturally invasive but also an excellent method to exclude hydrosalpinx.
Pelvic inflammatory disease (PID)
Inflammation often stays unnoticed and without symptoms. Thus, contagious sexual diseases and inflammation must eventually be detected if one wishes for a child. Most inflammation results from sexual, contagious diseases (mainly chlamydia) or due to the use of spirals. Inflammation is often responsible for the creation of hydrosalpinx as well.
In PID, inflammation in the uterus, tubes and ovaries may appear.
Uterine problems, such as myom, polyps or bad structure of the adhesions of the uterus mucous membrane (after operations or inflammation
Generally, diagnostic hysteroscopy and diagnostic laparoscopies, although minimally invasive, give information regarding all uterine problems.
Myom and polyps are mostly harmless; however, they should be removed by hysteroscopy depending on their position and size.
The reasons for an insufficient structure of the uterus mucous membrane may have immunologic and anatomic backgrounds. They are often linked to circulatory disorders or inflammation, or may even be the result of a surgery. The mucous membrane of the uterus may be medicinally supported.
Adhesions may be formed either after surgeries (like curettage, a scrape or a Caesarean section) or as the result of inflammation. These can often be treated with an invasive operation (a hysteroscopy or laparoscopy), yet they are not always completely removed.
Myoms should not always be removed; the size and the position, as well as the medical history of each woman, are decisive.
Cysts and PCOS
Polycystic ovarian syndrome (PCOS), also known as Stein-Leventhal syndrome, is attributed to hormonal disorders. In this process, cysts are formed in the ovaries, ovulation becomes rare, and male hormones (androgens) are produced in high doses. This disease often comes with obesity, diabetes or even amenorrhea. PCOS can be treated after a successful diagnosis, which is performed by ultrasound or hormonal examination.
Women with polycystic ovaries have multiple oocytes, most of which are immature and poor in quality
Endometriosis and adenomyosis are diseases of the uterus in which cells are formed in the abdominal area outside of the uterus (endometriosis) or in the muscular uterus wall (adenomyosis). In this case, inflammation and adhesions are responsible, and organs are often involved. The most frequent symptoms may be painful menstrual bleeding, pain during sexual intercourse, the creation of cysts and infertility.
A patient with endometriosis often has a poorer quality of ovaries and problems with their implantation.
An operative surgery before the implant pregnancy helps. Unfortunately, cysts and lesions often return. Therefore, a new intervention may be necessary.
Anamnesis, ultrasound images and often an MRI, blood examination and diagnostic laparoscopy contribute to the diagnosis.
Poor quality of oocytes or premature ovarian failure (POF)
Insufficiency of ovaries may come much earlier than menopause due to various reasons, which may include genetic reasons, environmental impacts, irradiation or chemotherapies. Early menopause means that a woman can get pregnant only with egg donation.
As age advances, the chances of a successful pregnancy decrease; at the same time, risks of genetic anomalies after birth increase.
The table below clearly indicates that the chances of a successful, natural pregnancy decrease as age increases; at 44 years old, a woman has a less than 5% chance to get pregnant naturally.
Source: Human Fertilization & Embryology Authority 2008
Disorders of the reproduction system after tumour diseases
Among these are mainly the ovarian reserves, which can often be affected after chemotherapy. Oncofertility provides a remedy, but women can also freeze their oocytes before irradiation.
Chronic diseases, such as diabetes, often have an impact on the reproduction system. Diagnosis involves an anamnesis and long-term therapies with several specialists collaborating.
Women with autoimmune diseases do not only face the challenge of achieving a pregnancy, but also maintaining it because the risk of a miscarriage is higher. Furthermore, stimulations may be harmful. Thus, a series of examinations and the collaboration of various specialists, such as rheumatologists, reproduction immunologists and haematologists, is necessary. In addition, these patients should be closely inspected during pregnancy. Often, there is no need for an autoimmune disease to have an “aggressive” immune system. A detailed screening of natural killer (NK) cells and other antibodies can be very helpful, especially in cases of miscarriages and disorders of implantation.
Your attending physician will, if necessary, proceed to further investigations and tests. The most necessary of them are comprised of the so-called immunologic screenings: antibodies screenings (such as the anti-ovarian antibody test and anti-zona pellucida); the function of the thyroid, including thyroid antibodies (Anti-TPA, Anti-TG); and excluding celiac disease.
ANA: anti-nuclear antibodies screening
APA: antiphospholid antibodies
Reproductive phenotypes: this test measures the percentage of lymphocytes in the blood, including CD-3, CD-4, CD-8, CD-19, CD-5, CD-56 and CD-16
NK analysis: NK cells are a type of blood corpuscle referred to as lymphocytes. They have a broad series of important functions, such as defence from infections and cancer. When these cells are extremely active or present in high numbers, they are connected with miscarriages and failures in implantation. Other lymphocytes, such as T-cells, play a role in the screening and are reckoned in the check up, just like alloimmunity.
Not least of all, an immunological screening comprises an endometrial biopsy to investigate CD57+ cells and regulatory T-cells so as to exclude other abnormalities of the endometrium (the lining of the uterus).
Toxoplasmosis and rubella must be excluded regularly before every treatment for a wished child.
A so-called cross match must be done in case of repeated miscarriages and disorders of implantation. In many cases, the female body does not create an immunity response to the father’s antigens and, thus, the immunity system of the mother repels the embryo. On these occasions, “active immunization” has been recommended since the 80s. Male lymphocytes are used to immunize the female (with an infusion). In this manner, the female’s immunity system is modified to accept a pregnancy.
Thorough investigations take place before treatment, including typification 1 and 2 and the detection of antibodies against HLA characteristics of the father.
Blood clotting disorders
Coagulation disorders can increasingly lead to miscarriages as well as difficulties of implantation that occur due to circulatory disorders.
Most often, this involves thrombophilia. This word means “thrombosis friend”, but also “tendency to thrombosis”, i.e., a predisposition to create blood clots. Thrombophilia is caused mostly by genetic predisposition, yet it can also be acquired. People with thrombophilia may eventually need treatment with anticoagulant drugs. Patients must be under the supervision of a doctor during pregnancy or in other extreme situations, such as certain surgeries.
The type of blood disease must be analyzed in cases of thrombophilia. Consequently, a specialist will perform several examinations. For instance, the level of fibrin (which is an important protein related to blood clotting) may be influenced by a lack of protein-C, protein-S, or antithrombin. The risks of clotting in veins and arteries are increased by homocysteine; therefore, it is necessary to have regular examinations to determine the level of homocysteine in connection to thrombophilia.
Although hereditary thrombophilia cannot be healed, it can be successfully monitored.
People with hyperhomocysteinemia should take folic acid, vitamin B6, vitamin B12 (cobalamin) supplements and anticoagulant drugs in order to prevent blood clots.
Women with multiple mutations are at a higher risk of miscarriage; however, it is known that certain mutations, such as MTHFR, are irrelevant to a prospective pregnancy.
In many cases, infertility or miscarriages have genetic causes. As a standard, karyotype, cystic fibrosis (CFTR) and thalassemia should be investigated; depending on indications, further investigations should be performed.
Genetic disorders can be linked to one of the partners; one can perform a pre-implantation genetic diagnosis by biopsy on the embryo.
· Obesity, nutrition disorders or malnutrition
· Excessive use of drugs or alcohol or other substances
· Other reasons (e.g., oxidative stress, poor general health)
· Anatomic disorders
A diagnostic hysteroscopy is minimally invasive and gives valuable information on the state of the uterus; thereby, small myoma or polyps are removed, and eventually dilation can be made. Most anatomic disorders are immediately detected.
REASONS FOR AND DIAGNOSIS OF MALE INFERTILITY
Hormonal tests are comprised of FSH, LH, FAI, testosterone and prolactin; an andrological examination is also performed.
Quality of the sperm
Initially, a sperm analysis is performed. The ideal abstinence before the examination is between two and (a maximum of) five days, with a frequency of 1–2 ejaculations before.
A sperm analysis does not examine merely the quantity of the ejaculation, but also, among other factors, the motility, its pH value and its morphology.
WHO criteria are used for the evaluation of the results. According to the latest version, morphology is judged by the “Krueger strict criteria”.
Morphology rates according to the Krueger strict criteria
The WHO standard values are:
Volume of ejaculation: 1.5 ml
Total sperm: 39 million
Concentration: 15 million/ml
Total motility: 40%
Proportion of vital sperm: 58%
Morphology % normal: at least 4%
According to the findings, a distinction of normospermia, oligospermia, asthenospermia, teratozoospermia, azoospermia or nekrozoospermia is made.
Components of the sperm
Further ejaculation tests are either the split ejaculate or pool ejaculate and the swim up test.
Genetic anomalies of the spermEven morphologically healthy sperm may be genetically unhealthy. Further investigations can be done to examine this case. The best-known tests are the DNA Fragmentation Index (DFI) and fluorescence in situ hybridization (FISH) test.
Anomalies of certain chromosomes can be detected with the FISH test.
In case of unfulfilled, desired conception, more investigations must be done to the male, (such as karyotyping, CFTR, and cystic fibrosis), as well as other microdeletions and translocations. A man should also be examined for thalassemia before beginning a donation programme.
The best-known ejaculation disorder is retrograde ejaculation, in which the flow of the sperm returns to the bladder. This may be caused by the use of medicines, chronic diseases, injuries or operations. In these cases, the sperm is directed to the testicles by means of a medical procedure.
InflammationA smear test can diagnose infections, as infections might also occur in men and affect their sperm quality. In particular, chlamydia and gonorrhoea lead to infertility due to the inflammation that blocks the epididymis, or they can cause infections to the prostate and testicles. Infections are mainly indicated by increased FSH values and/or low volume and motility. Successful treatment involves medication.
Chronic bacterial diseases, such as tuberculosis, may reduce sperm quality; therefore, a detailed medical history is very important for the andrologist.
VaricoceleA varicocele is a varicoce, i.e., an enlarged vein in the scrotum. Varicocele can be congenital or acquired and lead to pain in the scrotum and reduced fertility. Approximately 15% of men suffer from it, and 40% of subfertile men have varicocele.
Diagnosis is often performed by an andrological examination and an ultrasound, whereas the treatment is carried out with sclerotheraphy and, if necessary, an operation.
Often, antibodies develop against one’s own sperm, making spermatozoa useless. The MAR test can discover these kinds of antibodies. Additionally, immunologic reasons also comprise the action of the sperm in the cervical mucus of the partner. A post-coital test or sperm cervical mucus contact (SCMC) test is done for this purpose.
Environmental influences can have a negative impact on the quality of sperm. For men, it is also necessary to maintain fertility before starting irradiation or chemotherapy.
Other reasons resulting in bad sperm quality are often connected to age, unhealthy lifestyle (smoking, lack of exercise or overheating [e.g., by wheelchair users], being over- or underweight, and use of drugs such as steroids), or consequences of surgeries such as prostate or bladder. Likewise, men with erection dysfunction have difficulties producing sperm. Many of these cases may be treated either with long-term therapies or with minimally invasive procedures, such as FNA or TESE.
FNA sperm mappingBoth procedures occur under short general anaesthesia. It is an operation that achieves sperm retrieval directly from the testicles, for instance, in cases of azoospermia.
Furthermore, the fine needle aspiration (FNA) technique is also minimally invasive; its main difference from a biopsy is that the sperm is often found in the “pockets” and can be thoroughly investigated.