Fertility guide Everything you need to know before seeking medical advice for infertility treatment
ΙΝ Α FEW WORDS the following text is a valuable guide for those who wish to become parents but are concerned with infertility issues. This guide brings together all diagnostic tests available nowadays to assess fertility in men and women and gives you all necessary information, prior to visiting a specialist, about the steps you need to follow, in case you do not belong to those couples who achieve pregnancy after 12 months of unprotected sexual intercourse. And yet, it is advisable to visit a specialized gynecologist in the following cases: you are female and over 35 years old you experience problems with your period or other chronic gynecological problems you have known reasons which may lead to infertility you have a chronic medical condition (e.g. hypertension, diabetes, etc.) you have a family history of early menopause (mother, aunt, grandmother, etc.) 2
SINCE INFERTILITY CONCERNS BOTH PARTNERS AND NOT JUST ONE OF THEM, THE ONLY THING YOU NEED TO DO IS INFORM YOURSELF ABOUT ALL MEDICAL TESTS REQUIRED FOR BOTH MEN AND WOMEN. 3
FEMALE PARTNER a complete gynecological examination will provide all necessary and important information for an overall clinical picture; such examination includes the following: MEDICAL BACKGROUND During the first meeting with the specialized gynecologist you will need to state your medical background with information concerning your general health condition, such as potential chronic or hereditary diseases, allergies, medication intake, previous surgeries, etc. Emphasis will be placed on your personal gynecological background (age of first menstuation, duration of menstrual cycle and menstruation, pregnancy history, abortion or termination of pregnancy, fibroids, polyps, etc.). It is important to establish a sense of confidence between the gynecologist and the couple from the very first visit, so that no important information is omitted, and in order to ensure that the couple complies with the doctor s recommendations and instructions. The detection and subsequently the correction of any infertility problem requires coope-ration, teamwork and trust between the couple and the gynecologist. This can only be achieved gradually, but it may yet be inspired by the very first meeting. MANUAL PELVIC EXAMINATION After taking your medical history, the gynecologist continues with the gynecological examination, which is performed by meticulously checking external genitalia, the vagina and the cervix and then by taking a pap smear and vaginal-cervical fluid for culture. 4
TEST PAP The pap smear is taken on a day where you are not menstruating; you should also avoid sexual intercourse the day before. You should begin having a pap smear taken on the onset of sexual activity (regardless of age) and then once a year. VAGINAL CULTURE TEST If the clinical examination shows a picture of vaginitis-cervicitis, the gynecologist shall take vaginal and cervical smear for the detection of the cause of inflammation (fungus, bacteria, mycoplasma, etc.), and in order to pursue targeted medical treatment and therapy. During infertility testing it is required to have all examinations performed as stated above, as it is known that certain microorganisms such as mycoplasma, ureaplasma and chlamydia consist causes of infertility. 5
VAGINAL ULTRASOUND Ultrasonography is the simplest way to diagnose and exclude gynecological diseases, such as uterine fibroids, endometriosis cysts, polycystic ovaries, adenomyosis, ovarian cysts, polyps, endometrial hyperplasia, anatomical abnormalities, tumors of the internal genitalia, etc. All the above are important information for both the diagnosis of infertility, and for further treatment. BREAST EXAMINATION The gynecological examination should always include palpation of the breasts by the doctor to detect any palpable masses or other pathological conditions (breast inflammation, inverted nipples, skin lesions, etc.). Depending on the findings of this clinical examination, your doctor shall recommend further testing with ultrasound and/or mammography. In particular, in women with a family history of breast cancer, obesity, polycystic ovary 6
syndrome and diabetes, mammography should first be done at the age of 35 years, while it is mandatory once a year for all women over 40 years of age. After breast examination is completed, so is the first contact with your doctor. However, the most important thing is that the first meeting defines a relationship of mutual trust between the couple and the doctor, in order to achieve the purpose of obtaining a healthy child. MEASUREMENT OF VITAMIN D The deficiency of vitamin D may contribute to infertility. The blood test for 25 hydroxyvitamin D is used to measure the levels of the storable form of vitamin D in the body. Normal values should range at least from 40-50 nanograms per milliliter. HORMONOLOGICAL TESTS Blood tests are carried out on the 2nd to the 5th day of the cycle. The first day of your period is considered to be the first day of the cycle. The hormones tested are the following: FSH LH Oestradiol These three hormones give us all information about the function of the ovaries and the woman s fertility levels. AMH/MIS This hormone shows the adequacy of ovarian follicles and also the quality of eggs produced. TSH This hormone controls the function of the thyroid gland, and is directly connected both to fertility and cycle disorders. PRL Disturbance in the production of this hormone is associated with infertility and potential menstruation problems. DEHA-S The hormone index of adrenal glands, whose proper functioning is essential to fertility. Δ4 androstendione An androgen produced by the ovaries; elevated values are associated with infertility. 7
HYSTERO- SALPINGOGRAPHY (HSG) It is a simple radiological examination which is done without anesthesia between the 6th and 11th day of the cycle. It gives us very important information about the following: permeability of the fallopian tubes (conditions such as blockage of the tubes or hydrosalpinx consist main causes of infertility) the uterine cavity, the place where the embryo is to be implanted the existence of any congenital defects from the birth of a woman, such as bicornuate uterus, the existence of endometrial diaphragm and acquired disorders (e.g. polyps in the intrauterine cavity, submucosal fibroids, endometrial adhesions). A hysterosalpingography may release spasms of the fallopian tubes; for this reason the prophylactic use of anticonvulsants and non-steroidal anti-inflammatory drugs is recommended. Preventive antibiotics are also administered one day before or the day of the examination. 8
Depending on the results of the tests as written above, the gynecologist may consider appropriate to perform a series of additional tests, such as: THROMBOPHILIA SCREENING Thrombophilia is a condition where the blood has an increased tendency to form clots, also called thrombosis, divided into congenital or acquired. Hereditary thrombophilia may occur when gene mutations exist; they may be detected using specific blood tests, known as molecular diagnosis of hereditary thrombophilia testing. Some of these genes are Factor V Leiden, G 20210 variant, Factor FVIII and MTHFR. Acquired thrombophilia refers to the presence of diseases or substances that enhance blood clotting and may cause thrombosis, such as cardiolipin and B2 glycoprotein antibodies and anticoagulant lupus, Protein C, Protein S, ATIII, APCR and homocysteine. LAPAROSCOPY Not all women need to be submitted to a laparoscopy surgery. Such procedure is advisable only in the existence of evidence and allows direct examination and complete check of the internal female genitals (ovaries, uterus, fallopian tubes), as well as other intra-abdominal organs (intestine, liver, gall bladder, etc.) in order to identify and overcome potential problems. Laparoscopy achieves accurate diagnosis of conditions which often cause fertility problems, such as endometriosis, adhesions (internal scar tissues from previous surgery or inflammation), ovarian cysts or fibroids. Indications for laparoscopy: Adhesiolysis Removal of endometrial cysts Removal of fibroids Removal of ovarian cysts Laparoscopic removal of hydrosalpinx During laparoscopy surgery, three or four incisions (0,5-1 cm) are performed in the abdominal area for the insertion of laparoscopic instruments and a high-resolution camera. To allow an overview of the abdominal organs adequate space is required, which is created by the introduction of carbon dioxide into the peritoneal cavity. The image of the laparoscopy camera is displayed on screens so the surgeon has an enlarged 9
high-resolution image of the intra-abdominal organs in order to detect and correct abnormalities. Laparoscopy surgery is preferred among other procedures because it offers: short hospitalization (usually without the need for an overnight stay in the clinic) rapid recovery and return to daily activities (work, family commitments etc.) less postoperative pain better aesthetic results safety and much lower frequency of postoperative infections simultaneous detailed check of the organs in the abdominal area (through magnified and high-resolution image) HYSTEROSCOPY Hysteroscopy is a minor operation that allows direct examination of the uterine cavity using a hysteroscope and is performed only when indication exists. It does not require admission and overnight stay in the clinic, and it can be performed with or without anesthesia. The hysteroscope is inserted through the cervix into the uterine cavity and featuring a camera it offers the possibility of a direct review. If intrauterine polyps or adhesions are detected, they may be removed during the examination itself, if considered necessary. Any submucosal fibroids projecting into the uterine cavity and signs of endometrial inflammation can also be detected. 10
MALE PARTNER it is required that the male partner be also submitted to a complete examination of his reproductive system, including the following: SPERM ANALYSIS & SPERM CULTURE The partner should give a semen sample for sperm analysis. For more reliable results, semen for analysis should be collected after sexual abstinence of 3-4 days, not including the day of last intercourse and the day of sperm collection. Proper stimulation before collection is also required, so the presence and participation of the female partner is often advisable, if her partner wishes so. Before collecting the semen thorough washing of the genital area and hands is required. When ejaculate is discharged after masturbation, it is collected in a sterile container, which may either be purchased at a pharmacist s (similar to a urine collection container) or supplied by the sperm analysis laboratory. 11
The collection of semen can be done in a designated area available in all laboratories, or at home. If the collection is made at home, care is required when transferring the semen sample from home to the lab, so it maintains body temperature. This is achieved by placing the container in contact with the body during transportation or by wrapping the container with cotton wool and aluminium foil. Most importantly, transportation should not exceed one hour from the time of collection until the time of delivery to the laboratory. In case bacteria are detected in sperm culture, special treatment is required by taking appropriate antibiotics based on the susceptibility testing. As regards the values of the sperm parameters, in case they are lower than normal, semen analysis should be repeated with a time lapse of at least 15 days. If the second semen analysis shows that the parameters of sperm are lower than normal range (as defined by the World Health Organization), the sperm is characterized abnormal and further testing is recommended depending on the pathology. The male partner may undergo the following additional tests: Urological examination Doppler ultrasound of the scrotum Hormonal test Cystic fibrosis screening Sperm fragmentation UROLOGICAL EXAMINATION Clinical examination by a specialized andrologist or urologist for the detection of all pathological conditions which may result to a corresponding abnormal semen analysis, such as hypoplastic or atrophic testicles, the cryptorchidism etc. DOPPLER ULTRASOUND OF THE SCROTUM It is a non-invasive examination for the assessment of the testicles, the epididymis and the blood flow to the testicles. No specific preparation is required for the examination, after which you may resume your daily activities without any restrictions. If there is an abnormal finding, the examiner shall advise, give you further instructions and inform you on the appropriate options for treatment. HORMONAL TESTS In the framework of male fertility testing, it is necessary to measure the levels of certain hormones which may directly or indirectly affect the production of sperm. The main hormones to be tested are testosterone, FSH, LH, prolactin, TSH, estradiol and 12
cortisol. The analysis of the male hormonal profile is important when considering the reasons for which a person has reduced sperm count, when no other apparent reason exists, e.g. varicocele, testicular cancer, ejaculatory duct obstruction etc. The reduced size of testicles or insufficiently developed secondary male sexual characteristics (penis size, pubic hair, decreased muscle mass, lack of body hair, etc.) also require hormonal investigation. SPERM DNA FRAGMENTATION Sperm DNA fragmentation is nowadays one of the causes of male infertility. Simple parameters of sperm analysis, such as concentration, motility, morphology, are unable to detect sperm fragmentation. Moreover, samples showing normal values are very likely to have high fragmentation rates. 13
The high degree of DNA fragmentation may appear as an inhibiting factor of a successful pregnancy to the extend that any fertility treatment followed by the female partner becomes irrelevant. Several studies have shown that elevated levels of sperm DNA fragmentation relate to reduced pregnancy and birth rates, poor quality embryos and increased miscarriage rates. High rates of sperm DNA fragmentation can be caused by factors such as: infections smoking exposure to environmental pollutants certain occupations (eg driving) old age malnutrition and obesity the increase in testicular temperature (eg by laptops) use of drugs high fever varicocele cancer and treatments thereof Only a small amount of semen is required for the examination; after appropriate processing in the laboratory, sperm cells with fragmented DNA are detected and obtain a different morphology compared to those with intact DNA. The test results are expressed as DNA Fragmentation Index-% DFI (percentage of sperm cells with fragmented DNA). Depending on such percentage, they are divided into the following categories: < 15% DFI high fertility potentials > 15% to < 30% DFI good fertility potentials > 30% DFI low fertility potentials The results are considered normal when the sperm fragmentation index or DFI (%) is below 30%. Normal pregnancies occur even in couples where the male partner has a high percentage of sperm DNA fragmentation, yet with reduced chance of pregnancy and an increased risk of miscarriage. Is there a treatment for sperm DNA fragmentation? A number of good habits and practices may significantly contribute to enhancing fertility if adopted by infertile men to limit the reduction of sperm fragmentation, such as: smoking cessation diet rich in antioxidants, since oxidative stress is the main culprit for DNA fragmentation avoidance of certain drugs test for potential urinary tract infection a healthy diet consultation by the treating physician on vitamins and antioxidant supplements. 14
BOTH PARTNERS apart from the specialized tests concerning each partner separately, there is a series of tests which need to be performed jointly, as follows: MOLECULAR TEST FOR THE DETECTION OF CHLAMYDIA, UREAPLASMA, MYCOPLASMA Chlamydia, oureaplasma and mycoplasma are the most common sexually transmitted diseases. Chlamydia and particularly chlamydia trachomatis is the most common sexually transmitted disease. Mycoplasma, mainly 15
mycoplasma hominis, and ureaplasma urealyticum are bacteria often detected in female genitalia and are transmitted by sexual contact. Their existence may impair fertility. Although their presence can be detected by culture of vaginal and cervical fluid, culture detection of such bacteria gives false negative results at a rate of 40%. The most reliable method is the detection of the DNA of such microorganisms using a specific polymerase chain reaction (PCR) on a sample of vaginal and cervical fluid or tissue from the uterine cavity. KARYOTYPE BLOOD TEST The picture of a person s chromosomes is called a karyotype. The normal human karyotype consists of 46 chromosomes (23 pairs), two of which determine the person s gender. The karyotype of peripheral blood lymphocytes enables the testing of all chromosomes for possible existence of numerical and structural chromosome abnormalities and rearrangements. Since cytogenetic abnormalities associated with both male and female infertility, classical karyotype concerns couples with infertility problems, with two or more abortions during the first trimester of pregnancy and previous failed IVF attempts. The detection of such abnormalities is essential for the proper planning of a subsequent pregnancy which can either occur spontaneously or with assisted reproductive techniques. Peripheral blood karyotype must be performed by couples whose family background includes: a. people with: chromosomal abnormalities; mental retardation of unknown cause multiple miscarriages and neonatal death primary or secondary amenorrhea premature menopause abnormal sperm morphology (azoospermia, oligospermia) abnormal clinical phenotype (delayed growth spurt or gigantism, physical abnormalities, mental retardation) b. couples with: infertility of unknown cause (inability to conceive spontaneously or with assisted reproduction techniques) multiple miscarriages or neonatal mortality background due to unidentified cause child with diagnosed chromosomal anomaly diagnosed structural chromosomal abnormalities in the karyotype of the fetal amniotic fluid 16
CYSTIC FIBROSIS SCREENING Cystic fibrosis is the second most common genetic disease in Greece after thalassaemia, and the first among Caucasians. This disease is caused by mutations in the CFTR gene (cystic fibrosis transmembane conductance regulator) with a recessive inherited trait. This means that the carriers of the mutated gene are entirely healthy, but have a 50% probability of transferring the gene mutation to their offspring. The disease has a wide range of symptoms both in severity, and in scale (respiratory, digestive and other systems of the body). This means that there exist mild variations of the CFTR gene that do not lead to the distinct pathological phenotype of the disease and are simply related to a hypersensitivity of the respiratory system (e.g. frequent respiratory infections). Additionally, men with cystic fibrosis are infertile and in percentage of 20-40% are often carriers of a single abnormal CFTR gene and thus considered clinically healthy. By today s standards in Greece, the screening test should be carried out in all high-risk groups, but also in those couples willing to have a child. In the latter case, the screening should be first performed to the pregnant woman to specify whether she is a carrier of a mutation of cystic fibrosis. If the mother is found to be a carrier of such mutation, then the father should undergo extended testing for mutations, since the risk for a child to be born with the disease is greatly increased. It should be noted that a large number of couples with male infertility should be submitted simultaneously to genetic testing for mutations associated with cystic fibrosis: a significant percentage of men who have obstructive azoospermia and undergo ICSI techniques are carriers of the CFTR gene mutation. 17
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